Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson’s disease

Rey, Nolwen L.; Steiner, Jennifer A.; Maroof, Nazia; Luk, Kelvin C.; Madaj, Zachary; Trojanowski, John Q.; Lee, Virginia M.‐Y.; Brundin, Patrik

doi:10.1084/jem.20160368

Cited by 336 publications

(448 citation statements)

References 61 publications

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“…In monkeys, proteins extracted from human brains with LP (that would contain ␣-SYN fibrils and other LP proteins) also can retrogradely propagate from the striatum after injection (Recasens et al, 2014). More recent work has shown spreading from the olfactory bulb (Rey et al, 2016). Although there are a lot of questions about these experiments and their interpretation (Sacino et al, 2016;Uchihara and Giasson, 2016;Walsh and Selkoe, 2016), they do demonstrate that extracellular ␣-SYN fibrils can be taken up, retrogradely (and possibly anterogradely) transported, and induce Lewy-like pathology (and cell death).…”

Section: Braak Reduxmentioning

confidence: 99%

Parkinson's Disease Is Not Simply a Prion Disorder

2017

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The notion that prion-like spreading of misfolded ␣-synuclein (␣-SYN) causes Parkinson's disease (PD) has received a great deal of attention. Although attractive in its simplicity, the hypothesis is difficult to reconcile with postmortem analysis of human brains and connectome-mapping studies. An alternative hypothesis is that PD pathology is governed by regional or cell-autonomous factors. Although these factors provide an explanation for the pattern of neuronal loss in PD, they do not readily explain the apparently staged distribution of Lewy pathology in many PD brains, the feature of the disease that initially motivated the spreading hypothesis by Braak and colleagues. While each hypothesis alone has its shortcomings, a synthesis of the two can explain much of what we know about the etiopathology of PD.

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Section: Braak Reduxmentioning

confidence: 99%

Parkinson's Disease Is Not Simply a Prion Disorder

2017

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“…Mice from the following genetic backgrounds have been used successfully with the PFF-seeding paradigm: C57Bl/6J [55, 42], C57Bl/6/ C3H [30, 56], CD-1 (57], and C3H/HeJ [35]. Sprague-Dawley rats have also been used successfully for the aSyn PFF model [34, 52].…”

Section: Considerations For the Use Of Alpha-synuclein Pre-formed Fibmentioning

confidence: 99%

Best Practices for Generating and Using Alpha-Synuclein Pre-Formed Fibrils to Model Parkinson’s Disease in Rodents

Polinski

Volpicelli‐Daley

Sortwell

et al. 2018

JPD

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185

197

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Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting approximately one-percent of the population over the age of sixty. Although many animal models have been developed to study this disease, each model presents its own advantages and caveats. A unique new model has arisen to study the role of alpha-synuclein (aSyn) in the pathogenesis of PD. This model involves the conversion of recombinant monomeric aSyn protein to a fibrillar form—the aSyn pre-formed fibril (aSyn PFF)—which is then injected into the brain or introduced to the media in culture. Although many groups have successfully adopted and replicated the aSyn PFF model, issues with generating consistent pathology have been reported by investigators. To improve the replicability of this model and diminish these issues, The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has enlisted the help of field leaders who performed key experiments to establish the aSyn PFF model to provide the research community with guidelines and practical tips for improving the robustness and success of this model. Specifically, we identify key pitfalls and suggestions for avoiding these mistakes as they relate to generating the aSyn PFFs from monomeric protein, validating the formation of pathogenic aSyn PFFs, and using the aSyn PFFs in vivo or in vitro to model PD. With this additional information, adoption and use of the aSyn PFF model should present fewer challenges, resulting in a robust and widely available model of PD.

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“…According to the “Braak hypothesis”, PD pathology is thought to start from the periphery (gut or nose), and progress until it reaches the brain [4, 5, 49], spreading in a prion-like manner [20, 29, 36]. However, this hypothesis is still controversial, and the molecular mechanisms underlying this phenomenon are not fully understood [25].…”

Section: Introductionmentioning

confidence: 99%

The effects of the novel A53E alpha-synuclein mutation on its oligomerization and aggregation

Lázaro

Dias

Čarija

et al. 2016

acta neuropathol commun

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α-synuclein (aSyn) is associated with both sporadic and familial forms of Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease. In particular, multiplications and point mutations in the gene encoding for aSyn cause familial forms of PD. Moreover, the accumulation of aSyn in Lewy Bodies and Lewy neurites in disorders such as PD, dementia with Lewy bodies, or multiple system atrophy, suggests aSyn misfolding and aggregation plays an important role in these disorders, collectively known as synucleinopathies. The exact function of aSyn remains unclear, but it is known to be associated with vesicles and membranes, and to have an impact on important cellular functions such as intracellular trafficking and protein degradation systems, leading to cellular pathologies that can be readily studied in cell-based models. Thus, understanding the molecular effects of aSyn point mutations may provide important insight into the molecular mechanisms underlying disease onset.We investigated the effect of the recently identified A53E aSyn mutation. Combining in vitro studies with studies in cell models, we found that this mutation reduces aSyn aggregation and increases proteasome activity, altering normal proteostasis.We observed that, in our experimental paradigms, the A53E mutation affects specific steps of the aggregation process of aSyn and different cellular processes, providing novel ideas about the molecular mechanisms involved in synucleinopathies.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0402-8) contains supplementary material, which is available to authorized users.

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Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson’s disease

Abstract: Rey et al. generate a mouse model for the spatial propagation of α-synuclein pathology that mimics prodromal Parkinson's disease.

Cited by 336 publications

References 61 publications

Parkinson's Disease Is Not Simply a Prion Disorder

Parkinson's Disease Is Not Simply a Prion Disorder

Best Practices for Generating and Using Alpha-Synuclein Pre-Formed Fibrils to Model Parkinson’s Disease in Rodents

The effects of the novel A53E alpha-synuclein mutation on its oligomerization and aggregation

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