α-Synuclein and the Molecular Mechanisms of Lewy Body Formation in Parkinson's Disease

2002 ◽  
Vol 103 (s47) ◽  
pp. 2P-3P
Author(s):  
AR Saha ◽  
DP Hanger ◽  
BH Anderton
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Molecular Mechanisms ◽  
Body Formation

scholarly journals Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases

2021 ◽  
Author(s):  
Rahel Feleke ◽  
Regina H. Reynolds ◽  
Amy M. Smith ◽  
Bension Tilley ◽  
Sarah A. Gagliano Taliun ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Lewy Body ◽  
Molecular Mechanisms ◽  
Lewy Bodies ◽  
Subsequent Development ◽  
Lewy Body Dementia ◽  
Anterior Cingulate ◽  
Lewy Body Diseases

AbstractParkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular “window” of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.

scholarly journals Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy Body diseases

2021 ◽  
Author(s):  
Rahel Feleke ◽  
Regina H. Reynolds ◽  
Amy Smith ◽  
Bension Tilley ◽  
Sarah A. Gagliano Taliun ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Lewy Body ◽  
Molecular Mechanisms ◽  
Lewy Bodies ◽  
Subsequent Development ◽  
Lewy Body Dementia ◽  
Anterior Cingulate ◽  
Lewy Body Diseases

AbstractParkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular “window” of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.

scholarly journals Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

2019 ◽  
Author(s):  
Arlin Keo ◽  
Ahmed Mahfouz ◽  
Angela M.T. Ingrassia ◽  
Jean-Pascal Meneboo ◽  
Celine Villenet ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Brain Regions ◽  
Postmortem Brain ◽  
Brain Atlas ◽  
Dopamine Synthesis ◽  
Regional Vulnerability

AbstractThe molecular mechanisms underlying the caudal-to-rostral progression of Lewy body pathology in Parkinson’s disease (PD) remain poorly understood. Here, we aimed to unravel transcriptomic signatures across brain regions involved in Braak Lewy body stages in non-neurological controls and PD donors. Using human postmortem brain datasets of non-neurological adults from the Allen Human Brain Atlas, we identified expression patterns related to PD progression, including genes found in PD genome-wide associations studies: SNCA, ZNF184, BAP1, SH3GL2, ELOVL7, and SCARB2. We confirmed these patterns in two datasets of non-neurological subjects (Genotype-Tissue Expression project and UK Brain Expression Consortium) and found altered patterns in two datasets of PD patients. Additionally, co-expression analysis across vulnerable regions identified two modules associated with dopamine synthesis, the motor and immune system, blood-oxygen transport, and contained microglial and endothelial cell markers, respectively. Alterations in genes underlying these region-specific functions may contribute to the selective regional vulnerability in PD brains.

scholarly journals Differential Effects of Yeast NADH Dehydrogenase (Ndi1) Expression on Mitochondrial Function and Inclusion Formation in a Cell Culture Model of Sporadic Parkinson’s Disease

Biomolecules ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 119 ◽  
Author(s):  
Emily N. Cronin-Furman ◽  
Jennifer Barber-Singh ◽  
Kristen E. Bergquist ◽  
Takao Yagi ◽  
Patricia A. Trimmer
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Lewy Body ◽  
Complex I ◽  
Nadh Dehydrogenase ◽  
Lewy Bodies ◽  
Body Formation

Parkinson’s disease (PD) is a neurodegenerative disorder that exhibits aberrant protein aggregation and mitochondrial dysfunction. Ndi1, the yeast mitochondrial NADH dehydrogenase (complex I) enzyme, is a single subunit, internal matrix-facing protein. Previous studies have shown that Ndi1 expression leads to improved mitochondrial function in models of complex I-mediated mitochondrial dysfunction. The trans-mitochondrial cybrid cell model of PD was created by fusing mitochondrial DNA-depleted SH-SY5Y cells with platelets from a sporadic PD patient. PD cybrid cells reproduce the mitochondrial dysfunction observed in a patient’s brain and periphery and form intracellular, cybrid Lewy bodies comparable to Lewy bodies in PD brain. To improve mitochondrial function and alter the formation of protein aggregates, Ndi1 was expressed in PD cybrid cells and parent SH-SY5Y cells. We observed a dramatic increase in mitochondrial respiration, increased mitochondrial gene expression, and increased PGC-1α gene expression in PD cybrid cells expressing Ndi1. Total cellular aggregated protein content was decreased but Ndi1 expression was insufficient to prevent cybrid Lewy body formation. Ndi1 expression leads to improved mitochondrial function and biogenesis signaling, both processes that could improve neuron survival during disease. However, other aspects of PD pathology such as cybrid Lewy body formation were not reduced. Consequently, resolution of mitochondrial dysfunction alone may not be sufficient to overcome other aspects of PD-related cellular pathology.

Transcriptional activation of p62/A170/ZIP during the formation of the aggregates: possible mechanisms and the role in Lewy body formation in Parkinson's disease

2004 ◽  
Vol 1012 (1-2) ◽  
pp. 42-51 ◽  
Author(s):  
Kazuhiro Nakaso ◽  
Yuko Yoshimoto ◽  
Toshiya Nakano ◽  
Takao Takeshima ◽  
Yoko Fukuhara ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcriptional Activation ◽  
Lewy Body ◽  
Body Formation
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