The Role of -Synuclein in Neurodegenerative Diseases: >From Molecular Pathways in Disease to Therapeutic Approaches

Abstract

Parkinson disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer's disease (AD). The formation of the cytoplasmic inclusions named "Lewy bodies" in the brain, considered to be a marker for neuronal degeneration in PD and dementia with Lewy bodies. However, Lewy bodies (LBs) are also observed in approximately 60 percent of both sporadic and familial cases with AD. LBs consist of fibrils mainly formed by post-translational modified α-synuclein (α-syn) protein. The modifications can be truncation, phosphorylation, nitration and mono-, di-, or tri-ubiquitination. Development of disease seems to be linked to events that increase the concentration of α-syn or cause its chemical modification, either of which can accelerate α-syn aggregation. Examples of such events include increased copy number of genes, decreased rate of degradation via the proteasome or other proteases, or modified forms of α-syn. As the aggregation of α-syn in the brain has been strongly implicated as a critical step in the development of several neurodegenerative diseases, the current search for disease-modifying drugs is focused on modification of the process of α-syn deposition in the brain. Recently researchers have screened and designed various molecules that are selectively focused on inhibiting or preventing α-syn aggregation and toxicity. Another strategy that has emerged is to target α-syn expression as a potential therapy for neurodegenerative diseases associated with LBs.

Characterizing Gene and Protein Crosstalks in Subjects at Risk of Developing Alzheimer’s Disease: A New Computational Approach

“…Similarly, the enrichment of metabolic pathways, organismal systems including nervous and immune system pathways, and common signaling pathways of the environmental information processing category is also expected and well-supported in the literature [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68]. Interestingly, several genetic information processing pathways, including cell cycle regulation and DNA replication and repair, were found to be enriched.…”

Effect of Parkin on methamphetamine‐induced α‐synuclein degradation dysfunction in vitro and in vivo

“…α‐syn is a neuroprotein widely expressed in the brain and is involved in various neurodegenerative diseases (Al‐Mansoori, Hasan, Al‐Hayani, & El‐Agnaf, ; Melki, ). Studies have reported that various structural forms of pathological state α‐syn, such as fibrils, fibers, oligomers, and amorphous oligomers, and their posttranslational modifications, such as phosphorylation, nitration, and ubiquitination, are neurotoxic (Chen & Feany, ; Cremades et al, ).…”

Lewy body dementias

“…Numerous pathways and targets are being explored for Parkinson’s disease and Alzheimer’s disease, and strategies targeting the misfolding of proteins such as tau, amyloid, and α-synuclein are also likely to be relevant for dementia with Lewy bodies and Parkinson’s disease dementia. Modulating α-synuclein toxicity, for example by targeting heat shock proteins 156,157 or by manipulating chaperone-mediated autophagy, 158 are promising strategies. Alternative strategies include potential neuroprotective drugs such as adenosine-receptor blockers, monoamine oxidase inhibitors, antioxidative drugs, nerve growth factor, and stem-cell therapy, and multi-target drugs with neuroprotective and neurorestorative activity.…”