scholarly journals The Role of Cholesterol in α‐Synuclein and Lewy Body Pathology in GBA1 Parkinson's Disease

2020 ◽  
Author(s):  
Patricia García‐Sanz ◽  
Johannes Aerts ◽  
Rosario Moratalla
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Lewy Body Pathology

scholarly journals A Matrigel-based 3D construct of SH-SY5Y cells models the α-synuclein pathologies of Parkinson's disease

2022 ◽  
Author(s):  
Zhao-Feng Li ◽  
Lei Cui ◽  
Mi-Mi Jin ◽  
Dong-Yan Hu ◽  
Xiao-Gang Hou ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Cultured Cells ◽  
Three Dimensional ◽  
Proteinase K ◽  
All Trans Retinoic Acid ◽  
Lewy Body Pathology ◽  
Rotenone Treatment ◽  
2D And 3D

Parkinson's disease (PD) is featured with α-synuclein-based Lewy body pathology, which however was difficult to observe in conventional two-dimensional (2D) cell culture and even in animal models. We herein aimed to develop a three-dimensional (3D) cellular model of PD to recapitulate the α-synuclein pathologies. All-trans-retinoic acid-differentiated human SH-SY5Y cells and Matrigel were optimized for 3D construction. The 3D cultured cells displayed higher tyrosine hydroxylase expression and improved dopaminergic-like phenotypes than 2D cells as suggested by RNA-sequencing analyses. Multiple forms of α-synuclein, including monomer, low and high molecular weight oligomers, were differentially present in the 2D and 3D cells, but mostly remained unchanged upon the MPP+ or rotenone treatment. Phosphorylated α-synuclein was accumulated and detergent-insoluble α-synuclein fraction was observed in the neurotoxin-treated 3D cells. Importantly, Lewy body-like inclusions were captured in the 3D system, including proteinase K-resistant α-synuclein aggregates, ubiquitin aggregation, β-amyloid and β-sheet protein deposition. The study provides a unique and convenient 3D model of PD which recapitulates critical α-synuclein pathologies and should be useful in multiple PD-associated applications.

scholarly journals The emerging role of α-synuclein truncation in aggregation and disease

2020 ◽  
Vol 295 (30) ◽  
pp. 10224-10244 ◽  
Author(s):  
Zachary A. Sorrentino ◽  
Benoit I. Giasson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Multiple System Atrophy ◽  
Lewy Body ◽  
Critical Role ◽  
Lewy Body Dementia ◽  
Proteolytic Processing ◽  
Neuronal Protein ◽  
Preventative Strategy

α-Synuclein (αsyn) is an abundant brain neuronal protein that can misfold and polymerize to form toxic fibrils coalescing into pathologic inclusions in neurodegenerative diseases, including Parkinson's disease, Lewy body dementia, and multiple system atrophy. These fibrils may induce further αsyn misfolding and propagation of pathologic fibrils in a prion-like process. It is unclear why αsyn initially misfolds, but a growing body of literature suggests a critical role of partial proteolytic processing resulting in various truncations of the highly charged and flexible carboxyl-terminal region. This review aims to 1) summarize recent evidence that disease-specific proteolytic truncations of αsyn occur in Parkinson's disease, Lewy body dementia, and multiple system atrophy and animal disease models; 2) provide mechanistic insights on how truncation of the amino and carboxyl regions of αsyn may modulate the propensity of αsyn to pathologically misfold; 3) compare experiments evaluating the prion-like properties of truncated forms of αsyn in various models with implications for disease progression; 4) assess uniquely toxic properties imparted to αsyn upon truncation; and 5) discuss pathways through which truncated αsyn forms and therapies targeted to interrupt them. Cumulatively, it is evident that truncation of αsyn, particularly carboxyl truncation that can be augmented by dysfunctional proteostasis, dramatically potentiates the propensity of αsyn to pathologically misfold into uniquely toxic fibrils with modulated prion-like seeding activity. Therapeutic strategies and experimental paradigms should operate under the assumption that truncation of αsyn is likely occurring in both initial and progressive disease stages, and preventing truncation may be an effective preventative strategy against pathologic inclusion formation.

scholarly journals MMP13 Expression Is Increased Following Mutant α-Synuclein Exposure and Promotes Inflammatory Responses in Microglia

2020 ◽  
Vol 14 ◽  
Author(s):  
Kathryn Sánchez ◽  
Kathleen Maguire-Zeiss
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Receptor Activation ◽  
Proinflammatory Response ◽  
Molecular Pattern ◽  
Lewy Body Pathology ◽  
Acid Protein

α-Synuclein is a 140-amino acid protein that readily misfolds and is associated with the Lewy body pathology found in sporadic and genetic forms of Parkinson's disease. We and others have shown that wild-type α-synuclein is a damage-associated molecular pattern that directly elicits a proinflammatory response in microglia through toll-like receptor activation. Here we investigated the direct effect of oligomeric mutant α-synuclein (A53T) on microglia morphology and activation. We found that misfolded A53T increased quantitative measures of amoeboid cell morphology, NFκB nuclear translocation and the expression of prototypical proinflammatory molecules. We also demonstrated that A53T increased expression of MMP13, a matrix metalloproteinase that remodels the extracellular matrix. To better understand the role of MMP13 in synucleinopathies, we further characterized the role of MMP13 in microglial signaling. We showed exposure of microglia to MMP13 induced a change in morphology and promoted the release of TNFα and MMP9. Notably, IL1β was not released indicating that the pathway involved in MMP13 activation of microglia may be different than the A53T pathway. Lastly, MMP13 increased the expression of CD68 suggesting that the lysosomal pathway might be altered by this MMP. Taken together this study shows that mutant α-synuclein directly induces a proinflammatory phenotype in microglia, which includes the expression of MMP13. In turn, MMP13 directly alters microglia supporting the need for multi-target therapies to treat Parkinson's disease patients.

scholarly journals Parkinson's disease susceptibility variants and severity of Lewy body pathology

2017 ◽  
Vol 44 ◽  
pp. 79-84 ◽  
Author(s):  
Michael G. Heckman ◽  
Koji Kasanuki ◽  
Nancy N. Diehl ◽  
Shunsuke Koga ◽  
Alexandra Soto ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Disease Susceptibility ◽  
Lewy Body Pathology

scholarly journals Spinal Lewy body pathology in older adults without an antemortem diagnosis of Parkinson's disease

2017 ◽  
Vol 28 (4) ◽  
pp. 560-568 ◽  
Author(s):  
Aron S. Buchman ◽  
Sukriti Nag ◽  
Sue E. Leurgans ◽  
Jared Miller ◽  
Veronique G. J. M. VanderHorst ◽  
...  
Keyword(s):  
Older Adults ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Lewy Body Pathology

Lewy body pathology involves the olfactory cells in Parkinson's disease and related disorders

2016 ◽  
Vol 31 (1) ◽  
pp. 135-138 ◽  
Author(s):  
Yuko Saito ◽  
Ayako Shioya ◽  
Terunori Sano ◽  
Hiroyuki Sumikura ◽  
Miho Murata ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Lewy Body Pathology ◽  
Olfactory Cells

scholarly journals Divergent α-synuclein solubility and aggregation properties in G2019S LRRK2 Parkinson's disease brains with Lewy Body pathology compared to idiopathic cases

2013 ◽  
Vol 58 ◽  
pp. 183-190 ◽  
Author(s):  
Adamantios Mamais ◽  
Meera Raja ◽  
Claudia Manzoni ◽  
Sybille Dihanich ◽  
Andrew Lees ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Lewy Body Pathology
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