MSA prions exhibit remarkable stability and resistance to inactivation

Woerman, Amanda L.; Kazmi, Sabeen A.; Patel, Smita S.; Freyman, Yevgeniy; Oehler, Abby; Aoyagi, Atsushi; Mordes, Daniel A.; Halliday, Glenda M.; Middleton, Lefkos T.; Gentleman, Steve; Olson, Steven H.; Prusiner, Stanley B.

doi:10.1007/s00401-017-1762-2

Cited by 78 publications

(75 citation statements)

References 55 publications

(92 reference statements)

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“…Indeed, these results can be replicated by inoculating homogenate from the first transplanted rat brain into a second rat brain (Prusiner et al, 2015). Similar results can be found when the rat is exposed peripherally (like peritoneal cavity) to the homogenates of MSA brains (Woerman et al, 2018). Nevertheless, some issues need to be taken into account, like the fact that these results could not be obtained in wild-type (WT) mice (Prusiner et al, 2015).…”

Section: Prion-like Characteristics Of α-Synsupporting

confidence: 52%

Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles

et al. 2020

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Alpha-synuclein (α-syn) is localized in cellular organelles of most neurons, but many of its physiological functions are only partially understood. α-syn accumulation is associated with Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy as well as other synucleinopathies; however, the exact pathomechanisms that underlie these neurodegenerative diseases remain elusive. In this review, we describe what is known about α-syn function and pathophysiological changes in different cellular structures and organelles, including what is known about its behavior as a prionlike protein. We summarize current knowledge of α-syn and its pathological forms, covering its effect on each organelle, including aggregation and toxicity in different model systems, with special interest on the mitochondria due to its relevance during the apoptotic process of dopaminergic neurons. Moreover, we explore the effect that α-syn exerts by interacting with chromatin remodeling proteins that add or remove histone marks, up-regulate its own expression, and resume the impairment that α-syn induces in vesicular traffic by interacting with the endoplasmic reticulum. We then recapitulate the events that lead to Golgi apparatus fragmentation, caused by the presence of α-syn. Finally, we report the recent findings about the accumulation of α-syn, indirectly produced by the endolysosomal system. In conclusion, many important steps into the understanding of α-syn have been made using in vivo and in vitro models; however, the time is right to start integrating observational studies with mechanistic models of α-syn interactions, in order to look at a more complete picture of the pathophysiological processes underlying α-synucleinopathies.

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Section: Prion-like Characteristics Of α-Synsupporting

confidence: 52%

Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles

et al. 2020

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“…Moreover, recent experiments in cell and animal models use preformed SYN fibrils or brain homogenates from human LBD subjects to induce spread of SYN pathology that results in neuron loss and dysfunction as well as motor phenotypes which further supports this theory. Most recently, separate SYN species have been identified that may have different “strain‐like” properties, with certain preparations being additionally capable of cross‐seeding either tau or Aβ and others leading to MSA‐type pathologies . However, the core prion feature of infectivity has not clearly been demonstrated for LBD or AD in humans …”

Section: The Role Of Alpha‐synuclein In Lbd Pathogenesismentioning

confidence: 99%

“…Most recently, separate SYN species have been identified that may have different "strain-like" properties, with certain preparations being additionally capable of crossseeding either tau [54][55][56] or Aβ 57 and others leading to MSAtype pathologies. [58][59][60] However, the core prion feature of infectivity has not clearly been demonstrated for LBD or AD in humans. 61 Many autopsy studies have shown a correlation of LP with motor disease severity in PD.…”

Section: The Role Of Alpha-synuclein In Lbd Pathogenesismentioning

confidence: 99%

Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases

2019

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PD, PD with dementia, and dementia with Lewy bodies are clinical syndromes characterized by the neuropathological accumulation of alpha‐synuclein in the CNS that represent a clinicopathological spectrum known as Lewy body disorders. These clinical entities have marked heterogeneity of motor and nonmotor symptoms with highly variable disease progression. The biological basis for this clinical heterogeneity remains poorly understood. Previous attempts to subtype patients within the spectrum of Lewy body disorders have centered on clinical features, but converging evidence from studies of neuropathology and ante mortem biomarkers, including CSF, neuroimaging, and genetic studies, suggest that Alzheimer's disease beta‐amyloid and tau copathology strongly influence clinical heterogeneity and prognosis in Lewy body disorders. Here, we review previous clinical biomarker and autopsy studies of Lewy body disorders and propose that Alzheimer's disease copathology is one of several likely pathological contributors to clinical heterogeneity of Lewy body disorders, and that such pathology can be assessed in vivo. Future work integrating harmonized assessments and genetics in PD, PD with dementia, and dementia with Lewy bodies patients followed to autopsy will be critical to further refine the classification of Lewy body disorders into biologically distinct endophenotypes. This approach will help facilitate clinical trial design for both symptomatic and disease‐modifying therapies to target more homogenous subsets of Lewy body disorders patients with similar prognosis and underlying biology. © 2019 International Parkinson and Movement Disorder Society

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“…In PD, PDD, and DLB patients, α-synuclein accumulates in neurons as Lewy bodies and Lewy neurites (2). Recent studies demonstrate that MSA is unequivocally caused by α-synuclein prions, which are misfolded proteins that undergo self-propagation and are capable of transmitting disease to transgenic (Tg) mice (3)(4)(5)(6). Using TgM83 +/− mice, which express human α-synuclein with the familial A53T mutation, both intracranial (3,5) and peripheral inoculation (6) of brain homogenate from a total of 17 MSA patients induced neurological disease in the animals.…”

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confidence: 99%

Familial Parkinson’s point mutation abolishes multiple system atrophy prion replication

Woerman

Kazmi

Patel

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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In the neurodegenerative disease multiple system atrophy (MSA), α-synuclein misfolds into a self-templating conformation to become a prion. To compare the biological activity of α-synuclein prions in MSA and Parkinson's disease (PD), we developed nine α-synuclein−YFP cell lines expressing point mutations responsible for inherited PD. MSA prions robustly infected wild-type, A30P, and A53T α-synuclein-YFP cells, but they were unable to replicate in cells expressing the E46K mutation. Coexpression of the A53T and E46K mutations was unable to rescue MSA prion infection in vitro, establishing that MSA α-synuclein prions are conformationally distinct from the misfolded α-synuclein in PD patients. This observation may have profound implications for developing treatments for neurodegenerative diseases.ultiple system atrophy (MSA) is a rapidly progressing neurodegenerative disease resulting in dysfunction of the autonomic nervous system and disrupted motor function. The pathological hallmark of MSA is the presence of α-synuclein aggregates that coalesce into glial cytoplasmic inclusions (GCIs) in oligodendrocytes (1). MSA is one of four synucleinopathies, the other three being Parkinson's disease (PD), Parkinson's disease with dementia (PDD), and dementia with Lewy bodies (DLB). In PD, PDD, and DLB patients, α-synuclein accumulates in neurons as Lewy bodies and Lewy neurites (2). Recent studies demonstrate that MSA is unequivocally caused by α-synuclein prions, which are misfolded proteins that undergo self-propagation and are capable of transmitting disease to transgenic (Tg) mice (3-6). Using TgM83 +/− mice, which express human α-synuclein with the familial A53T mutation, both intracranial (3, 5) and peripheral inoculation (6) of brain homogenate from a total of 17 MSA patients induced neurological disease in the animals. In addition, α-synuclein prions isolated from MSA patients propagated in cultured HEK cells that express mutant human α-synuclein*A53T fused to YFP (α-syn140*A53T−YFP) (4). While PD transmission studies have induced α-synuclein neuropathology (7-9), attempts to transmit disease to TgM83 +/− mice or to infect α-syn140*A53T−YFP cells have been unsuccessful (5), suggesting that distinct conformations of misfolded α-synuclein or α-synuclein prion strains may be responsible for these diseases.To study the strain-specific properties of α-synuclein prions in MSA patients and to reconcile the differences between PD and MSA prions, we conducted a series of studies to investigate the effect of inherited PD point mutations on MSA prion replication. In addition to the original WT (α-syn140-YFP) and α-syn140*A53T-YFP cells first reported in 2015 (4), we generated seven additional HEK cell lines expressing single mutations (A30P and E46K), double mutations (A30P,A53T and E46K,A53T), and truncated α-synuclein*A53T (residues 1-95, 1-97, and 29-97). After measuring MSA prion infection in the WT, A30P, and A53T cell lines, we were surprised to observe that the E46K mutation prevented the replication of MSA prions in vi...

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MSA prions exhibit remarkable stability and resistance to inactivation

Cited by 78 publications

References 55 publications

Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles

Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles

Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases

Familial Parkinson’s point mutation abolishes multiple system atrophy prion replication

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