Although the precise physiological function of aSyn is still unclear, several studies suggest that aSyn is involved in the regulation of synaptic membrane processes and in neurotransmitter release through interactions with members of the SNARE family Tsigelny et al. Surprisingly, studies in aSyn knockout mice revealed that aSyn is not essential for synapse formation and cell survival Bisaglia et al.
The primary sequence of aSyn can be divided in three distinct domains: the amino-terminal domain N-terminal, residues 1—60 , the central domain residues 61—95 and the carboxy-terminal domain C-terminal domain, residues 96— The lipid composition of membranes is critical for aSyn binding. It seems that lipid rafts serve as a platform, which promotes aSyn binding and oligomerization Davidson et al. Schematic illustration of aSyn and tau proteins. The primary sequence of aSyn can be divided in three distinct domains: the amino-terminal domain N-terminal, residues 1—60 , the central domain also known as NAC domain residues 61—95 , and the carboxy-terminal domain C-terminal domain, residues 96— Both the N-terminal and NAC domain are characterized part of the membrane binding domain.
The C-terminal domain is rich in acidic residues 15 acidic amino acids: 10 Glu and 5 Asp residues and lacks defined secondary structure. The primary sequence of the full-length human tau isoform can be divided in the N-terminal domain also known as projection domain, the central domain which is the microtubule binding domain MTBD and the C-terminal tail. The N-terminal consists of the acidic part encoded by exons 2 and 3 E called inserts 1 and 2 N , followed by the proline-rich region PRR.
The C-terminal tail is enriched in positively charged residues. Importantly, all the known mutations associated with familial forms of PD are clustered within the N-terminal region of aSyn Polymeropoulos et al. Interestingly, aSyn was reported to be acetylated at the N-terminus in cells, an essential modification that protects its native conformation against pathological aggregation Iyer et al.
Interestingly, one phosphorylation site is present in the NAC domain—the S87 residue. S87 phosphorylation is increased in synucleinopathies, leading to inhibition of aSyn oligomerization which influences synuclein-membrane interactions Paleologou et al. The carboxy-terminal domain C-terminal domain is characterized by a non-defined structure Bisaglia et al.
This suggests the implication of phosphorylation in the aggregation propensity. These PTMs may act by modulating the structure, the physiological functions and the toxicity of aSyn. Furthermore, they can modulate protein-protein interactions, interaction with metal ions Paik et al. Moreover, the region plays a protective role against aggregation, due to the presence of all the five proline Pro residues of the protein Meuvis et al. Changes in the charge or the hydrophobicity by residue substitution as well as deletion of the C-terminal lead to accelerated aggregation of aSyn in vitro Hoyer et al.
As mentioned above, aSyn has the ability to bind to acidic membranes. Under physiological conditions aSyn exists in a dynamic equilibrium between the unfolded cytosolic and the membrane—bound state Burre et al. However, the exact nature of those toxic species remains unknown, and is still unclear whether aggregation initiates from its lipid-bound part or from the unstructured cytosolic protein Trexler and Rhoades, ; Chen et al.
Tau was first discovered associated with microtubules, together with other microtubule-associated proteins Weingarten et al. For this reason, it was included in the family of microtubule-associated proteins MAPs. There are six different isoforms of tau in the central nervous system, generated from the MAPT gene, as a result of alternative splicing. These isoforms range from to amino acids Neve et al.
Each of the six tau isoforms differs in their primary structure due to the content of three 3R or four repeats 4R of the microtubule binding domains in the C-terminal region, in combination with the presence or absence of one N1 or two N2 amino acid inserts in the N-terminal part of the protein. Since the isoforms are differentially expressed in the brain during development, and stimulate microtubule assembly with different efficiencies, possibly possess particular physiological roles and implicated at different biological activities Utton et al.
Importantly, in neurodegenerative diseases such as AD and PD, modified proportions of the different tau isoforms have been observed Bre and Karsenti, ; Avila et al. Tau stabilizes the polymerization of microtubules through the three or four MTBR repeats in case of the longest isoform Drubin and Kirschner, ; Maccioni et al.
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Under physiological conditions, in mature neurons, all tau protein is likely to be microtubule bound Ackmann et al. The primary sequence of tau consists of the N-terminal domain, half of which is enriched in acidic residues, followed by a proline-rich region and the positively charged C-terminal tail. The protein can also undergo different types of PTMs like phosphorylation, ubiquitination, acetylation, glycation, methylation, truncation of the N- or C-terminal regions or nitration Avila et al. Most of these sites are located within the proline-rich region in close proximity to the MTBR domains and in the C-terminal tail Figure 1Bi Buee et al.
The phosphorylation state of the protein affects the secondary structure and, subsequently, regulates all the normal and abnormal functions like development, interaction with different protein partners such as microtubules, localization, aggregation, and spreading Camero et al. In principle, a normal and strictly controlled level of phosphorylation is required for the appropriate function of the protein, while the pathological state is characterized by hyperphosphorylation that leads the tau to lose its biological activity Kopke et al.
The deposition of hyperphosphorylated tau in insoluble filaments in the brain is a pathological hallmark not only of AD but also of related neurodegenerative diseases, known as tauopathies, including frontotemporal dementias FTD like Pick's Disease and argyrophilic grain disease, progressive supranuclear palsy, and corticobasal degeneration Grundke-Iqbal et al. Major differences between tauopathies are the deposition of different isoforms of tau Rademakers et al.
In Pick's disease 3R isoforms are predominant, and the arrangement of tau is different than that in inclusions found in AD Falcon et al. On the other hand, in the other tauopathies only the 4R isoform is present in the filaments Goedert, In AD brains, the abnormally hyperphosphorylated tau is presented in the cytosol inhibiting the assembly of tubulin and disrupting microtubules. Furthermore, as a result of self-assembly is accumulated into neurofibrillary deposits in neurons and glial cells Iqbal et al.
In sporadic and familial FTD, several mutations have been identified in the tau gene. Some of these mutations are thought to disrupt the normal binding of tau to tubulin resulting in pathological deposits of hyperphosphorylated tau Rademakers et al. As with aSyn, it is believed that in a variety of tauopathies, the most toxic species are oligomeric, but the controversy is still not fully resolved.
These oligomeric species are non-fibrillar, multimeric, soluble forms of the protein Haase et al. Examples of tauopathies where oligomers have been proposed as the toxic species include AD, corticobasal degeneration, Pick's disease, and progressive supranuclear palsy Maeda et al. Prion diseases are infectious diseases that can be transmitted horizontally between individuals of the same or even different species Costanzo and Zurzolo, ; Kizhakke et al.
Other proteins may manifest prion-like behavior. The stable propagation of different misfolded protein conformations was established as a defining feature of the prion paradigm and of the prion-like spreading of pathology Jucker and Walker, Importantly, both aSyn and tau appear to spread in a prion-like manner Holmes et al. However, different structural features may affect the way they propagate. Each protein has a characteristic core that undergoes conformational changes and may lead to aggregation. Differences in these regions may lead to differences in the aggregated species formed.
Whether aSyn and tau spreading have an infectious nature like that of the prion protein remains unclear. In general, protein infectivity depends on several factors, such as irreversibility of misfolded protein assemblies, the efficiency by which precursor polypeptides are recruited into aggregates, the clearance of the aggregates, and the efficiency of the spreading of misfolded protein proteins Brundin et al.
Post mortem analysis of human brains revealed progression of neuropathology in a series of stages Braak et al. Initially, the lesions start in the olfactory bulb, anterior olfactory nucleus, and dorsal motor nucleus of the vagus Ordonez et al. During the second stage, pathology spreads to the lower raphe nuclei, the magnocellular portions of the reticular formation and the locus coeruleus Prots et al. In the third stage, the pathology reaches the midbrain, affecting fundamentally the substantia nigra pars compacta Braak et al.
Pathology spreads then to the cortex during the fourth stage. In this stage the mesocortex is affected whilst the neocortex is unaffected Braak et al. In the last two stages, pathology reaches the neocortex. Initially affecting the prefrontal neocortex and then moving to the premotor areas, the primary sensory areas and the primary motor field Braak et al.
It has been found in the choroid plexus, where it may be produced by the choroid cells that participate in its transport between the blood and cerebrospinal fluid Bellani et al. Additional studies showed the spreading of aSyn from diseased to healthy tissue. Several PD patients underwent embryonic neuronal cell transplantation developed the disease years after the surgery. Interestingly, in these studies, the presence of cytosolic aSyn phosphorylated at S was also shown Kordower et al.
These studies, together with the Braak staging hypothesis, were considered strong evidence in favor of the prion-like spreading of aSyn pathology in the brain Olanow and Prusiner, Following these findings, several new studies revealed that aSyn can propagate from host to grafted tissue Desplats et al.
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A different set of studies showed how the administration of brain lysates from multiple system atrophy MSA patients into TgM83 mice brain leads to transmission in a way that is reminiscent of the transmission of the prion protein in chimpanzee brains in a model of Kuru Gajdusek et al. This process was proposed to happen through cell-to-cell transmission following not only cell connectivity, and may reach parts of the CNS away from the injection site Luk et al. Furthermore, 9 months after the inoculation of pathological aSyn from sarkosyl-insoluble fractions from cortical brain tissue from MSA patients, aSyn aggregates were found in the side contralateral to the administration Bernis et al.
Interestingly, in all these experiments human material leads to disease in different species. The transmission among different species is one of the main characteristics of prion proteins. Another argument in favor of the prion-like behavior of aSyn is that, under certain conditions, aSyn can assemble aberrantly forming prion strains Guo et al.
When aSyn fibrils are inoculated in Wistar rats they act as seeds imprinting their intrinsic structures, turning monomeric aSyn into fibrils. When aSyn ribbons were injected, endogenous aSyn in Wistar rats acquired this specific conformation Breydo et al. Furthermore, when two different strains of aSyn pre formed fibrils were inoculated in mice, endogenous aSyn acquired the structure of the strain inoculated Peelaerts et al. Also, assemblies such as fibrils and ribbons can cross the blood-brain barrier and reach the CNS after intravenous injection Uversky, b.
Several mechanisms have been put forward to explain the spreading of aSyn between cells. These include membrane pores Stockl et al. Possible mechanisms associated with the cell-to-cell transmission of aSyn and tau. The release of tau and aSyn is thought to take place via different mechanisms: 1 aSyn oligomers may form pore-like structures that penetrate the plasma membrane.
These structures may act as non-selective channels, leading to the release of aSyn. Both proteins monomers or fibrils bind HSPGs at the cell surface, and then get internalized; 9 both proteins may be taken up by endocytosis. In these cells, aSyn is released through a calcium-dependent non-conventional pathway. Treatment with compounds that interfere with the normal function of endosomes result to significant changes in the extracellular levels of aSyn. Thus, the release pathway of aSyn is dependent on the integrity of the endosomal compartment Emmanouilidou et al.
Release can also happen through exosomes. They can be released through budding forming a small vesicle or formed inside the multivesicular body, which fuses then with the cell membrane releasing its vesicles into the extracellular space Beaudoin and Grondin, ; Denzer et al. Membrane carrier proteins like the secretory carrier membrane protein 5 can also participate in the release of aSyn through exosomes Yang et al. These release processes can happen from either the cell soma or the synaptic button, as aSyn is also transmitted trans-synaptically Danzer et al.
Interestingly, mutant forms of aSyn such as the H50Q and the G51D are more prone to be released via exosomes and other types of extracellular vesicles than the wild type protein Falcon et al. In addition, aSyn can also reach the extracellular space, not only by active mechanisms, but also passively by leakage through damaged cell membranes or by cell impairments.
This process can be exacerbated by aSyn itself, as its interactions and fibrillization may disrupt cell membrane integrity Volles and Lansbury, ; Chaudhary et al. Internalization can then happen through the aforementioned mechanisms. During pinocytosis, aSyn is internalized in a dynamin-dependent process which seems to be more relevant for monomeric than for aggregated aSyn Hansen et al. Furthermore, the endocytic process of aSyn internalization is a dynamin-dependent process, but not clathrin-dependent Uversky, a. Tunneling nanotubes are F-actin containing membranous bridges that connect the cytoplasm of remote cells, first described in PC12 cells Abounit and Zurzolo, Fibrillar aSyn can spread from cell to cell in a prion-like way through tunneling nanotubes by mechanisms such as intercellular trafficking of lysosomes Abounit et al.
This happens not only among neuronal cells, but also in pericytes and astrocytes Dieriks et al. Changes in aggregation propensity like the ones mentioned above lead to changes in the internalization and clearance of aSyn Lee et al. These pores can be formed by aSyn itself in its oligomeric form, as it crosses the cell membrane leading to the formation of octameric ring structures, being the mutant A53T more prone to do it Ma et al.
The formation of these pores by aSyn is related with its binding properties to membranes and lipid layers. The association with these membranes leads to changes in membrane conductance which result to changes in its pore activity formation Tosatto et al. In fact, binding of aSyn to the cell membrane causes permeabilization of the cell membrane by decreasing the lipid order Stockl et al.
This process also facilitates passive diffusion of the protein. Passive diffusion is a mechanism that allows exclusively the internalization of monomers Lee et al. It is noteworthy that changes in the amphipatic N-terminus lead to an altered binding of aSyn to membranes. This results in abnormal vesicle interactions and changes the conformation of the vesicles, affecting aSyn spreading Taneva et al. Out of the three known membrane proteins described to interact with aSyn, only the LAG3 and PrP C mediate in its internalization through endocytosis Chen et al. Interestingly, activation of PrPc receptor by extracellular aSyn oligomers also leads to the phosphorylation of Fyn kinase activating the NMDAR receptor in a process that is independent of pore formation and impairs hippocampal long term potentiation leading to cognitive impairment Diogenes et al.
Tau also progresses in a predictable manner throughout the CNS. In AD, tau starts its propagation in the transentorhinal region and progresses through the hippocampus, cortex and the superior temporal gyrus, finally reaching the neocortex Uversky, ; Braak et al. Nonetheless, particularly in FTD cases with Pick's disease type of tau pathology, atrophy progression starts in the frontal lobe and the hippocampus, then the temporal lobe and the insula, and finally pathology reaches areas of the parietal lobe Broe et al. Tau propagates trans-synaptically, mostly based on connectivity and not on proximity Ahmed et al.
This propagation happens mostly through afferent connections Iba et al. Although propagation happens mainly through afferent connections, small tau species can be transported anterogradely and retrogradely in neurons Wu et al. In PS transgenic mice, tau pre-formed fibrils lead to templated misfolding of tau in a prion-like manner along neuronal connections Stancu et al. When injected into the brain, aggregated PS tau present in brain homogenates from PS mice induces the spreading of filamentous tau pathology in ALZ17 mice Clavaguera et al.
Interestingly, the PS mutant spreads at least five times faster than the wild type WT tau Kundel et al. In normal conditions, purified human tau does not form protein assemblies Crowther et al. Polyanionic substances, especially glycosaminoglycans such as heparin or heparan sulfate proteoglicans HSPGs , promote tau aggregation, thereby accelerating the formation of amyloid tau fibrils Montejo de Garcini et al.
All six tau isoforms are able to aggregate even though, in vitro , the 4R isoforms are more prone to aggregation than the 3R isoforms Zhong et al. Once the protein forms assemblies, these can act as seeds for the generation of new assemblies, even when they are applied extracellularly, spreading subsequently to other cells Goedert and Spillantini, Tau spreads from cell to cell through several different putative mechanisms, similar to those proposed for aSyn Guo and Lee, ; Tardivel et al.
A mechanism that was proposed to be more frequent for tau than for aSyn, is the internalization of the protein via macropinocytosis Lee et al. Different types of HSPGs have been described to facilitate cellular internalization of aSyn and tau in vitro and in vivo and blocking their expression diminishes the internalization of tau and aSyn monomer and aggregates Holmes et al. Oligomers and short fibrils which bind to membranes can be internalized through receptor-independent mechanisms. On the other hand, monomers, long fibrils, or long filaments, are more dependent on receptor-mediated mechanisms Wu et al.
Extracellular tau can also affect the accumulation of endogenous tau in a way that is dependent on the tau isoform found in the extracellular space. In addition, it has been shown that oligomeric 0N4R tau induces the accumulation of endogenous tau to a small extent, while oligomeric 0N3R, 1N3R, and 1N4R tau do not stimulate accumulation of intracellular tau Swanson et al.
Detachment of tau from microtubules, e. Certain extracellular forms of tau, especially soluble forms composed mostly of monomers and small oligomers, appear to be cytotoxic through muscarinic receptor activation, involving the tissue non-specific alkaline phosphatase Sebastian-Serrano et al. Extracellular tau, mainly truncated forms, can also contribute to synaptic dysfunction Brandt et al.
Interestingly, these truncated forms have been reported to undergo truncation from the C-terminus to inner regions and have been linked to the pathogenesis of AD Basurto-Islas et al. So far, two major sites of truncation have been studied, especially truncation at residues E and D Interestingly, the truncation at D is not only found in AD brains, but also in Pick's disease brains, where C-terminal truncated tau has been proposed to be the main isoform found in exosomes Mena et al.
Furthermore, overexpression of the projection domain of tau suppresses neuronal growth factor-induced neurite formation, contributing to synaptic dysfunction Brandt et al. The mechanisms by which aSyn and tau spread through the central nervous system are of utmost importance to understand the progression of PD and AD, respectively.
To study these mechanisms, several cell models of aSyn and tau spreading have been used in the last years. Different cell lines have been used to study specific mechanisms underlying the spreading of aSyn and tau pathology. For instance, the mouse neuroblastoma N2a cell line has been extensively used to study cell-to-cell spreading through exosomes Wang et al.
The cell-to-cell transmission through tunneling nanotubes has been studied in the cathecolaminergic CAD cell line Abounit et al. The C In recent years, animal models based in the administration of different forms of aSyn and tau in specific brain and peripheral areas have been used Table 3. The use of animal models enables us to address specific aspects of the spreading of aSyn or tau pathology, in particular those related to neuronal connectivity, or to the spreading between different organs Braak and Braak, ; Delacourte et al.
For aSyn, both mice and rats have been extensively used Hansen et al. Non-human primates have already been used to study the spreading of aSyn pathology Kirik et al. Interestingly, a lamprey model has been used to study the effects of several tau mutations in the progression of neurodegeneration Lee et al. Transgenic mice expressing mutant forms of aSyn, such as A53T and A30P, have also been used, and are proving useful for studying other synucleinopathies including MSA Giasson et al. For tau, the rTg mouse line, harboring the PL mutation, has been widely used Barghorn et al.
Additionally, injections of viral vectors have been also extensively used to induce aSyn and tau overexpression. In the case of aSyn, several studies reported the mimicking of relevant PD features, the progressive nature, and the spreading of pathology, in mice, rats, and non-human primates Kirik et al.
In the case of tau there are also models based on the use of viral vectors Klein et al. Tau and aSyn pathologies spread in a manner that is reminiscent of the process of prion spreading in prion diseases, whereby misfolded forms of the proteins can act as templates and induce the misfolding of normally structured proteins. The altered proteins can spread from cell to cell throughout the CNS, and possibly also between different organs through neuronal connections.
In contrast to prion diseases, in AD and PD there is still no definitive evidence for horizontal transmission of tau or aSyn pathologies, as these proteins have not been shown to be infectious. Additionally, the spreading of pathology in synucleinopathies and tauopathies seems to be slower than that observed in prion diseases, but the reason for this is still unknown Yekhlef et al.
The putative mechanisms involved in the spreading of both tau and aSyn are thought to be similar. One difference is that tau appears to have greater propensity to be internalized through macropinocytosis. From an anatomical point of view, aSyn and tau appear to spread from and to different locations, in patterns that are relatively predictable McCann et al.
In conclusion, through the use of different model systems, it is becoming evident that the spreading of aSyn and tau pathologies share similar mechanisms, and there is hope that a deeper understanding of those mechanisms may lead to the identification of novel targets for therapeutic intervention in various neurodegenerative diseases. EV and AD-M reviewed the literature and contributed equally to the design and writing of the manuscript. TO reviewed the final manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
National Center for Biotechnology Information , U. Journal List Front Mol Neurosci v. Front Mol Neurosci. Published online Apr Author information Article notes Copyright and License information Disclaimer. Received Jan 13; Accepted Apr 9. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Abstract Alzheimer's disease AD and Parkinson's disease PD are age-associated neurodegenerative disorders characterized by the misfolding and aggregation of alpha-synuclein aSyn and tau, respectively. Keywords: alpha-synuclein, Parkinson's disease, tau, Alzheimer's disease, spreading. Introduction Alzheimer's disease AD and Parkinson's disease PD are progressive, age-associated neurodegenerative disorders.
Open in a separate window. Figure 1. Tau Structure and Function Tau was first discovered associated with microtubules, together with other microtubule-associated proteins Weingarten et al. Prions and Prion-like Spreading of Pathology Prion diseases are infectious diseases that can be transmitted horizontally between individuals of the same or even different species Costanzo and Zurzolo, ; Kizhakke et al.
Spreading of aSyn Pathology aSyn neuropathology typically progresses in a predictable manner throughout the brain. Figure 2. Cell Models for Studying the Spreading of aSyn and Tau The mechanisms by which aSyn and tau spread through the central nervous system are of utmost importance to understand the progression of PD and AD, respectively. Table 1 Cell models used to study aSyn spreading.
Uptake is inhibited when clathrin heavy chain is silenced Kisos et al. Table 2 Cell models used to study tau spreading. Animal Models for Studying the Spreading of aSyn and Tau In recent years, animal models based in the administration of different forms of aSyn and tau in specific brain and peripheral areas have been used Table 3.
Table 3 Animal models used to study aSyn spreading. Absence of spreading for phosphor-aSyn in rats and marmosets Bourdenx et al. Uptake is inhibited by silencing the expression of clathrin heavy chain Kisos et al. Amyloidogenic h aSyn shows limited induction of neuronal aSyn inclusions Sacino et al. Table 4 Animal models used to study tau spreading. Exosomes from microglial culture, exosomes from mouse brain lysates PL Participation of microglia in the spreading of tau; mediation of exosomes Asai et al. Iba et al. Conclusions Tau and aSyn pathologies spread in a manner that is reminiscent of the process of prion spreading in prion diseases, whereby misfolded forms of the proteins can act as templates and induce the misfolding of normally structured proteins.
Author Contributions EV and AD-M reviewed the literature and contributed equally to the design and writing of the manuscript. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Footnotes Funding. References Abounit S. Tunneling nanotubes spread fibrillar alpha-synuclein by intercellular trafficking of lysosomes. EMBO J. Tunneling nanotubes: a possible highway in the spreading of tau and other prion-like proteins in neurodegenerative diseases.
Prion 10 , — Wiring through tunneling nanotubes—from electrical signals to organelle transfer. Cell Sci. Nonsaturable binding indicates clustering of tau on the microtubule surface in a paired helical filament-like conformation. A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity.
Acta Neuropathol. Amino acid sequence motifs and mechanistic features of the membrane translocation of alpha-synuclein. Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Phosphorylation of Ser is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo. Alpha-synuclein p.
H50Q, a novel pathogenic mutation for Parkinson's disease. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. The tau code. Aging Neurosci. Role of tau protein in both physiological and pathological conditions. Phosphorylation does not prompt, nor prevent, the formation of alpha-synuclein toxic species in a rat model of Parkinson's disease. Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer's disease.
Brain Res. Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry 39 , — The N-terminus of the intrinsically disordered protein alpha-synuclein triggers membrane binding and helix folding. Accumulation of aspartic acid and glutamic acidcleaved tau in neurofibrillary tangles correlates with progression in Alzheimer disease. Alpha-synuclein accumulates in Lewy bodies in Parkinson's disease and dementia with Lewy bodies but not in Alzheimer's disease beta-amyloid plaque cores. Shedding of vesicular material from the cell surface of eukaryotic cells: different cellular phenomena.
Acta , — The regulation of synaptic function by alpha-synuclein. Review: Parkinson's disease: from synaptic loss to connectome dysfunction. From alpha-synuclein to synaptic dysfunctions: new insights into the pathophysiology of Parkinson's disease. Defining long-range order and local disorder in native alpha-synuclein using residual dipolar couplings. Prion-like propagation of human brain-derived alpha-synuclein in transgenic mice expressing human wild-type alpha-synuclein. Structural insights on physiological functions and pathological effects of alpha-synuclein.
The microtubule-associated protein tau mediates the organization of microtubules and their dynamic exploration of actin-rich lamellipodia and filopodia of cortical growth cones. Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by alpha-synuclein overexpression. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry.
Neuropathological stageing of Alzheimer-related changes. Staging of brain pathology related to sporadic Parkinson's disease. Aging 24 , — Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. Normal host prion protein PrPC is required for scrapie spread within the central nervous system. Functional organization of microtubule-associated protein tau. Identification of regions which affect microtubule growth, nucleation, and bundle formation in vitro.
Interaction of tau with the neural plasma membrane mediated by tau's amino-terminal projection domain. Cell Biol. Effects of brain microtubule-associated proteins on microtubule dynamics and the nucleating activity of centrosomes. Cell Motil. Cytoskeleton 15 , 88— Alpha-synuclein misfolding and Parkinson's disease. Neurofibrillary tangles of Alzheimer's disease: an immunohistochemical study.
In This Article
Alzheimer's disease and tau proteins. Lancet 2 Staging disease severity in pathologically confirmed cases of frontotemporal dementia. Neurology 60 , — Interactions between metals and alpha-synuclein—function or artefact? FEBS J. Prion-like transmission of protein aggregates in neurodegenerative diseases. N-Terminal acetylation preserves alpha-synuclein from oligomerization by blocking intermolecular hydrogen bonds. ACS Chem. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders.
Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau. Lentiviral delivery of the human wild-type tau protein mediates a slow and progressive neurodegenerative tau pathology in the rat brain. Thermodynamics of the interaction between Alzheimer's disease related tau protein and DNA.
In vitro alpha-synuclein neurotoxicity and spreading among neurons and astrocytes using Lewy body extracts from Parkinson disease brains. Membrane interactions and fibrillization of alpha-synuclein play an essential role in membrane disruption. FEBS Lett. Cell 40 , — Structural characterization of toxic oligomers that are kinetically trapped during alpha-synuclein fibril formation. Genomics 26 , — Brain homogenates from human tauopathies induce tau inclusions in mouse brain.
Transmission and spreading of tauopathy in transgenic mouse brain. Peripheral administration of tau aggregates triggers intracerebral tauopathy in transgenic mice. The cell biology of prion-like spread of protein aggregates: mechanisms and implication in neurodegeneration. Assembly of Alzheimer-like filaments from full-length tau protein. Detecting tau in serum of transgenic animal models after tau immunotherapy treatment. Aging 37 , 58— Heat-shock protein 70 modulates toxic extracellular alpha-synuclein oligomers and rescues trans-synaptic toxicity.
Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73 , — The role of the prion protein in the internalization of alpha-synuclein amyloids.
Prion 12 , 23— Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of alpha-synuclein in midbrain dopamine neurons. The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease. Neurology 52 , — Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Loss of native alpha-synuclein multimerization by strategically mutating its amphipathic helix causes abnormal vesicle interactions in neuronal cells.
Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Aggregated alpha-synuclein transfer efficiently between cultured human neuron-like cells and localize to lysosomes. Tau protein function in living cells. Different tau species lead to heterogeneous tau pathology propagation and misfolding.
Neuron-to-neuron wild-type Tau protein transfer through a trans-synaptic mechanism: relevance to sporadic tauopathies. Multiple factors contribute to the peripheral induction of cerebral beta-amyloidosis. Aggregates from mutant and wild-type alpha-synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of beta-sheet and amyloid-like filaments.
Alpha-synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma. Biophysical characterization of intrinsically disordered proteins. Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. Exocytosis and spreading of normal and aberrant alpha-synuclein.
Brain Pathol. Long-term consequences of human alpha-synuclein overexpression in the primate ventral midbrain. Brain , — Severe alterations in lipid composition of frontal cortex lipid rafts from Parkinson's disease and incidental Parkinson's disease. Conformation determines the seeding potencies of native and recombinant Tau aggregates.
Structures of filaments from Pick's disease reveal a novel tau protein fold. Nature , — Lipid rafts mediate the synaptic localization of alpha-synuclein. Age-dependent cognitive decline and amygdala pathology in alpha-synuclein transgenic mice. Aging 28 , — Neuron-to-neuron transmission of alpha-synuclein fibrils through axonal transport. A nucleated assembly mechanism of Alzheimer paired helical filaments. Experimental transmission of a Kuru-like syndrome to chimpanzees.
Amyloid oligomerization of the Parkinson's disease related protein alpha-synuclein impacts on its curvature-membrane sensitivity. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Truncation of tau protein and its pathological significance in Alzheimer's disease.
Membrane-bound alpha-synuclein forms an extended helix: long-distance pulsed ESR measurements using vesicles, bicelles, and rodlike micelles. Characterization of tau oligomeric seeds in progressive supranuclear palsy. Soluble tau aggregates, not large fibrils, are the toxic species that display seeding and cross-seeding behavior. Protein Sci. Structure based aggregation studies reveal the presence of helix-rich intermediate during alpha-Synuclein aggregation.
Ordering Paper Back-Issues
Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34 , — Initiation and synergistic fibrillization of tau and alpha-synuclein. Science , — A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly. Alzheimer's and Parkinson's diseases: the prion concept in relation to assembled Abeta, tau, and alpha-synuclein.
Science Propagation of Tau aggregates. Brain 10 Identification of a novel microtubule binding and assembly domain in the developmentally regulated inter-repeat region of tau.
Release and uptake of pathologic alpha-synuclein. Cell Tissue Res. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. Abnormal phosphorylation of the microtubule-associated protein tau tau in Alzheimer cytoskeletal pathology. Distinct alpha-synuclein strains differentially promote tau inclusions in neurons. Cell , — Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles. Pseudophosphorylation of tau protein alters its ability for self-aggregation.
Membrane lipid co-aggregation with alpha-synuclein fibrils. Brain propagation of transduced alpha-synuclein involves non-fibrillar protein species and is enhanced in alpha-synuclein null mice. Networks of tau distribution in Alzheimer's disease. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proteopathic tau seeding predicts tauopathy in vivo. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats.
Mechanism of alpha-synuclein translocation through a VDAC nanopore revealed by energy landscape modeling of escape time distributions. Nanoscale 9 , — Rapid self-assembly of alpha-synuclein observed by in situ atomic force microscopy. Behind the curtain of tauopathy: a show of multiple players orchestrating tau toxicity. Life Sci. Tau pathology spread in PS19 tau transgenic mice following locus coeruleus LC injections of synthetic tau fibrils is determined by the LC's afferent and efferent connections.
Tau and neurodegenerative disease: the story so far. When a railroad is built through tribal lands, the event is at first greeted with curiosity. One day, a thirsty group of young Sioux pass by a railroad station and ask for water. The stationmaster refuses to serve them, which angers the group. When they return home and report how they were treated, a council is called to decide what to do.
Standing Bear remembers his mother grabbing an axe and following the men to the railroad track, where they tear up the rails, cut the ties, and haul the pieces away. In popular Westerns the presence of the railroad typically marks the beginning of the end.
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It points to the arrival of industrialization and capitalist development, which in turn signals the death of wilderness and the closing of the frontier. He regarded the frontier as an important dividing line between the so-called primitive and the civilized, and contended that American democracy emerged out of frontier conditions found in the region. Eventually the arrival of the railroad does take on new meanings for Standing Bear. In particular, it begins to signal threats to tribal sovereignty and increased territorial conflicts across the region.
Here, the forces of barbarism in need of enlightenment are the white populations whose industries have expanded across tribal spaces and who do not show respect or extend common courtesies to the people already residing in the land. The memoir likewise complicates the frontier thesis by indicating that the West was not the site of free lands or an empty space awaiting the arrival of white settlers, but was home to numerous indigenous people whose civilizations shaped and transformed the land long before the arrival of Europeans.
The stories were usually situated in lands that extend west of the Mississippi River to the Pacific Coast and typically took place between and , roughly the time Turner set as the closing of the frontier. The standardized plots tended to include stories about the building of the railway, tales of ranch life, narratives about the cattle empire, revenge tales, the cavalry and Indian story, and narratives about the clash between the outlaw and the marshal.
Guthrie Jr. The period saw the release of numerous Westerns by top directors including William S. Hart, Cecil B. While Westerns appear less frequently on the big screen, they are not less significant as a cinematic genre. As Andrew Patrick Nelson argues, Westerns today have been transformed into a new type of film production—as prestige dramas that are made in fewer numbers, but that are intended to win honors for A-list directors, writers, and actors during the awards season. Although the genre is sometimes dismissed as straightforwardly endorsing U.
In the work of indigenous writers such as N. In their novels, stories, essays, poetry, and memoirs, Native American writers frequently emphasize different philosophies and practices in creating more sustainable human relations with the nonhuman world. In her novel Ceremony , for instance, Laguna Pueblo author Leslie Marmon Silko foregrounds the power of indigenous ceremonies and oral narratives as a route to survival in the aftermath of disaster. There, he battles alcoholism while mourning the loss of his friend during the war. A recent anthology of scholarly essays on the literature of the West edited by Steven Frye, for instance, begins with a chronology starting in ce.
The timeline includes references to the first known irrigation system built in the region and lists a severe drought occurring in the Southwest from to Winner of a Pulitzer Prize, the novel is set in Oklahoma during the Great Depression and tells the story of the Joad family, tenant farmers who struggle to survive during the Dust Bowl years.
While the drought places numerous pressures on the family and the Depression intensifies their conditions of precarity, the Joads also face challenges caused by a modernizing system of agriculture that further disrupts their livelihoods. Treating climate as a character in its own right, the novel both genders and racializes eco-disaster.
While environmental catastrophe wreaks havoc on western lands and livelihoods, it also rewrites boundaries and hierarchies by dismantling the racial power of the ranchers. At another point, Charlie recalls previous populations who resided in Texas. Scholars have noted that environmental crisis can result in unpredictable ways, with some populations offering cooperation or support and others choosing to maintain the status quo by keeping in place systems of power.
The genre of speculative fiction addresses similar challenges. Set in San Francisco after nuclear war has devastated the biosphere, the novel was made into the cult classic film Blade Runner directed by Ridley Scott. Employing noir tropes in its depiction of the post-apocalyptic urban landscape, the story addresses a profoundly damaged environment ruled by powerful global corporation and describes the declining possibilities for the characters as well as the replicants, or the genetically enhanced artificial humans who increasingly populate this world.
In The Ecology of Fear , geographer Mike Davis chronicles the myriad disasters facing Los Angeles at the end of the 20th century in the wake of fire, earthquakes, mudslides, hyper-development of the built environment, and growing divisions between the wealthy and the poor. Many critics instead point to the importance of imagining worlds governed by more inclusive, equitable, and sustainable politics rather than one ruled by fears about divine punishment and retribution.
The survivors try to make new lives for themselves in a world where superstorms have wiped out large portions of the population and where a flu epidemic has left even more devastation. After written texts have migrated to e-readers, only a few are able to enjoy the world of books. Much of the challenge of rebuilding society thus involves imagining what sustainability might look like if more inclusive communities, critical thinking, political cooperation, and social freedoms were part of this environment.
The novel also reconceptualizes the nature essay, a genre that has played an important role in developing environmental awareness about the West. Gold, fame, citrus. They were feckless, yeah? During their road trip, Luz carries with her an impressive reading list, a canon of western literature that includes books by or about Sacajawea, Lewis and Clark, John Wesley Powell, John Muir, and William Mulholland, all of whom are figures whose lives intertwined with water and the development of the American West, either as guide, explorer, and conservationist, or, in the case of Mulholland, as the person responsible for building the infrastructure providing LA with its modern water supply.
Part of the difficult task for authors and critics thus becomes how to write the American West in the face of eco-disaster, how to determine what language and literary forms will be useful in making sense of the environmental disruptions and crises that are reshaping our world. When European explorers and Anglo-American tourists first arrived in the Southwest, they struggled to comprehend the geographical and climate challenges posed by the desert. As a way of making sense of the terrain, many writers described the space through a familiar language, using biblical imagery to situate the desert as a New World Holy Land waiting to be claimed by American Adams and Eves.
Describing the U. In a desert mirage? In challenging human understandings of the more-than-human world, Fuentes gestures toward a larger time frame and spatial awareness that in many ways anticipates recent developments in science and the environmental humanities. Since , Earth system specialists have argued that the human imprint on the biosphere has altered the planet to such a degree that we have now entered a new geologic time period, the Anthropocene, or the age of humans. Such a focus may render human agency nearly impossible, creating a falsely inclusive view of the species as uniformly and equally responsible while emptying local communities of any relevance or power to enact meaningful change.
Elihu Willsson was Personville, and he was almost the whole state. Most of its builders had gone in for gaudiness. Maybe they had been successful at first. When the main character returns to his hometown after it has been evacuated in the wake of industrial pollution, he considers ending his life because of the deadly consequences of the toxic product he helped develop.
In the novel, ecological disaster is thus understood to include a broad set of concerns such as pervasive racism, ongoing colonialism, and neoliberal economies. The environmental justice movement has brought increased attention to the manner in which ecological issues are often framed in narrow ways by mainstream organizations. The result is that popular environmentalism frequently ends up excluding people of color and working-class communities by focusing on landscapes of leisure, such as wilderness areas or national parks, rather than the spaces in which humans mostly live and work.
It contrasts the beauty of the California landscape with the harsh and toxic working conditions of migrant laborers in the Central Valley. The novel contrasts the experiences of two families in LA, the upper-middle-class Mossbacher household with America and Candido Rancon, undocumented workers from Mexico who cross the border in search of better lives. Asian American writers also configure disaster in broader terms by addressing the immigration restrictions that disrupted the development of Asian communities across the West. In these instances, disaster and western environments are recast and reinterpreted to include larger problems of racial violence, forced labor, and confiscated lands and property, as well as toxic work and living conditions.
In Radical Hope: Ethics in the Face of Cultural Devastation , philosopher Jonathan Lear turns to the autobiography of Crow leader Chief Plenty Coups — for the ways it describes the disappearance of bison in the late 19th century as marking the end of a way of life across the Northern Plains. Offering the concept of radical hope, Lear notes the challenges that appear when the conceptual foundations enabling a population to thrive no longer have meaning and points to the need for developing strategies to better address these crises.
As various scholars have pointed out and as some of the literature suggests, many of the popular narratives that have framed the American West do not provide sustainable ecological models for our present condition. While the region in settler colonial contexts has been defined in a contradictory manner as a land of opportunity and promise yet also a place that faces immanent demise, the West has also been understood in a different manner, as a space of diverse stories that address dwelling and encounters, conflict and loss, transformation and recovery, as well as a site of speculation and critical assessment about current and future catastrophes.
In this way, the literature of the West may be recognized as offering competing assessments of and numerous strategies for confronting the environmental disturbances, disasters, and transformations that have altered the region over time. Various fields of study have emerged through an engagement with the literature of the American West.
The rise of the new western history in the s associated with scholars such as Patricia Limerick, William Cronon, Richard White, and Donald Worster redirected studies of the region by pointing to how previous work tended to over-rely on the Turner thesis while underplaying racial differences and the environmental consequences of expansion. Influenced by developments in the new western history, literary critics such as Krista Comer, Neil Campbell, William Handley, and Nathaniel Lewis extended these discussions in their studies of regional literature.
When scholars trace the study of western American literature through the lens of environmental critique, they often note that it was at the annual meeting of the Western Literature Association in Reno, Nevada, that a group of scholars founded the study of eco-criticism, with The Ecocriticism Reader: Landmarks in Literary Ecology , edited by Cheryl Glotfelty and Harold Fromm , as the first significant collection published in the field.
The region has also played a central role in the transnational turn in American studies. Borderlands criticism, for instance, countered the frontier thesis in focusing on the West as a multicultural space and contact zone. Asian American and indigenous studies scholarship also helped usher in the transnational turn among Americanists. Western Literature Association. Resilience: A Journal of the Environmental Humanities. Association for the Study of Literature and the Environment. Adamson, Joni. Tucson: University of Arizona Press, Find this resource:.
Allmendinger, Blake, ed. Imagining the African American West. Lincoln: University of Nebraska Press, Bold, Christine. Oxford: Oxford University Press, Brady, Mary Pat. Campbell, Neil. Comer, Krista. Fitzsimmons, Lorna, ed. Asian American Literature and the Environment. New York: Routledge, Frye, Steven, ed. Cambridge, U. Gamber, John. Ethnic Literatures. Goodman, Audrey.
Handley, William R. True West: Authenticity and the American West. Johnson, Michael K. Kollin, Susan. Kollin, Susan, ed. A History of Western American Literature. Lewis, Nathaniel. Unsettling the Literary West: Authenticity and Authorship.