Intrastriatal alpha-synuclein fibrils in monkeys: spreading, imaging and neuropathological changes

Chu, Yaping; Muller, Scott; Tavares, Adriana; Barret, Olivier; Alagille, David; Seibyl, John; Tamagnan, Gilles; Marek, Kenneth; Luk, Kelvin C.; Trojanowski, John Q.; Lee, Virginia M.‐Y.; Kordower, Jeffrey H.

doi:10.1093/brain/awz296

Cited by 91 publications

(86 citation statements)

References 67 publications

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“…The stereotypic spread of Lewy bodies in PD from the rostral brain stem to the midbrain and eventually throughout the neocortex suggests a prion-like mechanism mediating propagation of protein aggregates from neuron to neuron [5]. This temporo-spatial spread of Lewy bodies correlates with clinical progression of PD and has been replicated in several animal models [6][7][8].…”

Section: Introductionmentioning

confidence: 84%

Glucocerebrosidase reduces the spread of protein aggregation in aDrosophila melanogastermodel of neurodegeneration by regulating proteins trafficked by extracellular vesicles

Jewett

Thomas

Phan

et al. 2020

Preprint

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Abnormal protein aggregation within neurons is a key pathologic feature of Parkinson's disease (PD). The spread of protein aggregates in the brain is associated with clinical disease progression, but how this occurs remains unclear. Mutations in the gene glucosidase, beta acid 1 (GBA), which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the most penetrant common genetic risk factor for PD and dementia with Lewy bodies, and also associate with faster disease progression. To explore the mechanism by which mutations in GBA influence pathogenesis of these diseases, we previously created a Drosophila model of GBA deficiency (Gba1b) that manifests neurodegeneration, motor and cognitive deficits, and accelerated protein aggregation. Proteomic analysis of Gba1b mutants revealed dysregulation of proteins involved in extracellular vesicle (EV) biology, and we found altered protein composition of EVs from Gba1b mutants. To further investigate this novel mechanism, we hypothesized that GBA may influence the spread of pathogenic protein aggregates throughout the brain via EVs. We found that protein aggregation is reduced cellautonomously and non-cell-autonomously by expressing wildtype GCase in specific tissues. In particular, accumulation of insoluble ubiquitinated proteins and Ref (2)P in the brains of Gba1b flies are reduced by ectopic expression of GCase in muscle tissue.Neuronal expression of GCase also cell-autonomously rescued protein aggregation in brain as well as non-cell-autonomously rescued protein aggregation in muscle. Musclespecific GBA expression rescued the elevated levels of EV-intrinsic proteins and Ref(2)P found in EVs from Gba1b flies. Genetically perturbing EV biogenesis in specific tissues in the absence of GCase revealed differential cell-autonomous effects on protein aggregation but could not replicate the non-cell-autonomous rescue observed with tissuespecific GBA expression. Additionally, we identified ectopically expressed GCase within isolated EVs. Together, our findings suggest that GCase deficiency mediates accelerated spread of protein aggregates between cells and tissues via dysregulated EVs, and EVmediated trafficking of GCase may partially account for the reduction in aggregate spread.

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Section: Introductionmentioning

confidence: 84%

Glucocerebrosidase reduces the spread of protein aggregation in aDrosophila melanogastermodel of neurodegeneration by regulating proteins trafficked by extracellular vesicles

Jewett

Thomas

Phan

et al. 2020

Preprint

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“…Subsequently, the aggregation of monomers into fibrils is induced and the fibrils are sonicated to generate short fibrils w h i c h a f t e r i n j e c t i o n , t r i g g e r t h e a g g r e g a t i o n , hyperphosphorylation and ubiquitination of endogenous a-Syn (Patterson et al, 2019). Intracerebral injection of a-Syn PFFs has been extended to rodents, both mice (Luk et al, 2012a;Masuda-Suzukake et al, 2013;Karampetsou et al, 2017;Milanese et al, 2018;Okuzumi et al, 2018;Patterson et al, 2019) and rats (Paumier et al, 2015;Harms et al, 2017;Thakur et al, 2017;Duffy et al, 2018b;Durante et al, 2019) and non-human primates (Shimozawa et al, 2017;Chu et al, 2019). PFFs have been mainly injected in the striatum (Luk et al, 2012a;Paumier et al, 2015;Karampetsou et al, 2017;Shimozawa et al, 2017;Duffy et al, 2018b;Milanese et al, 2018;Okuzumi et al, 2018;Chu et al, 2019;Durante et al, 2019;Patterson et al, 2019), the substantia nigra (Masuda-Suzukake et al, 2013;Harms et al, 2017) and the cortex (Luk et al, 2012b).…”

Section: Injection Of A-syn Pre-formed Fibrils or Pathological Extractsmentioning

confidence: 99%

“…It is well described that intracerebral inoculation of PFFs leads to the formation of pa-Syn-immunoreactive aggregates that are distributed both in the soma and neuronal processes. a-Syn inclusions exhibit different morphological features that resemble human Lewy bodies: from granules with cytoplasmic staining to compact and rounded structures with dark staining that fills entirely cells (Luk et al, 2012a;Paumier et al, 2015;Chu et al, 2019). Some studies have shown that these aggregates commonly colocalize with key markers of Lewy bodies, including ubiquitin and p62/proteasome 1 (Wakabayashi et al, 2013), and they are thioflavin S-positive and proteinase K-resistant, indicating that they share common properties with human Lewy bodies (Paumier et al, 2015;Chu et al, 2019).…”

Section: Injection Of A-syn Pre-formed Fibrils or Pathological Extractsmentioning

confidence: 99%

“…a-Syn inclusions exhibit different morphological features that resemble human Lewy bodies: from granules with cytoplasmic staining to compact and rounded structures with dark staining that fills entirely cells (Luk et al, 2012a;Paumier et al, 2015;Chu et al, 2019). Some studies have shown that these aggregates commonly colocalize with key markers of Lewy bodies, including ubiquitin and p62/proteasome 1 (Wakabayashi et al, 2013), and they are thioflavin S-positive and proteinase K-resistant, indicating that they share common properties with human Lewy bodies (Paumier et al, 2015;Chu et al, 2019). Our group has observed the presence of pa-Synimmunoreactive structures with similar morphological characteristics at 12 weeks after intrastriatal inoculation of human wild-type aSyn PFFs in the SNCA-OVX transgenic mouse model (Janezic et al, 2013; Figure 1).…”

Section: Injection Of A-syn Pre-formed Fibrils or Pathological Extractsmentioning

confidence: 99%

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Modeling Parkinson’s Disease With the Alpha-Synuclein Protein

et al. 2020

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Alpha-synuclein (a-Syn) is a key protein involved in Parkinson's disease (PD) pathology. PD is characterized by the loss of dopaminergic neuronal cells in the substantia nigra pars compacta and the abnormal accumulation and aggregation of a-Syn in the form of Lewy bodies and Lewy neurites. More precisely, the aggregation of a-Syn is associated with the dysfunctionality and degeneration of neurons in PD. Moreover, mutations in the SNCA gene, which encodes a-Syn, cause familial forms of PD and are the basis of sporadic PD risk. Given the role of the a-Syn protein in the pathology of PD, animal models that reflect the dopaminergic neuronal loss and the widespread and progressive formation of a-Syn aggregates in different areas of the brain constitute a valuable tool. Indeed, animal models of PD are important for understanding the molecular mechanisms of the disease and might contribute to the development and validation of new therapies. In the absence of animal models that faithfully reproduce human PD, in recent years, numerous animal models of PD based on a-Syn have been generated. In this review, we summarize the main features of the a-Syn pre-formed fibrils (PFFs) model and recombinant adenoassociated virus vector (rAAV) mediated a-Syn overexpression models, providing a detailed comparative analysis of both models. Here, we discuss how each model has contributed to our understanding of PD pathology and the advantages and weakness of each of them. Significance: Here, we show that injection of a-Syn PFFs and overexpression of a-Syn mediated by rAAV lead to a different pattern of PD pathology in rodents. First, a-Syn PFFs models trigger the Lewy body-like inclusions formation in brain regions directly interconnected with the injection site, suggesting that there is an inter-neuronal transmission of the a-Syn pathology. In contrast, rAAV-mediated a-Syn overexpression in the brain limits the a-Syn aggregates within the transduced neurons. Second, phosphorylated a-Syn inclusions obtained with rAAV are predominantly nuclear with a punctate appearance that becomes diffuse along the neuronal fibers, whereas a-Syn PFFs models lead to the formation of cytoplasmic aggregates of phosphorylated a-Syn reminiscent of Lewy bodies and Lewy neurites.

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“…This PFF injection induced the formation of α-syn-positive cytoplasmic inclusions in neurons of the striatum as well as interconnected regions such as the cortex, associated with a loss of dopaminergic neurons in the SN and motor dysfunctions [60], while a similar injection of soluble α-syn had no effect [61]. PFF also induced a progressive synucleinopathy after intracerebral injection into susceptible transgenic mice [62][63][64], and in non-human primate models [65]. In 2014, LB-enriched fractions purified from PD brains containing pathological aggregated α-syn were injected unilaterally in the SN and striatum of WT mice and non-human primates.…”

Section: The Prion-like Hypothesis As a Model Of α-Syn Pathogenicitymentioning

confidence: 96%

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

et al. 2020

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Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.

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Intrastriatal alpha-synuclein fibrils in monkeys: spreading, imaging and neuropathological changes

Cited by 91 publications

References 67 publications

Glucocerebrosidase reduces the spread of protein aggregation in aDrosophila melanogastermodel of neurodegeneration by regulating proteins trafficked by extracellular vesicles

Glucocerebrosidase reduces the spread of protein aggregation in aDrosophila melanogastermodel of neurodegeneration by regulating proteins trafficked by extracellular vesicles

Modeling Parkinson’s Disease With the Alpha-Synuclein Protein

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

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