Title:Alpha-synuclein, Proteotoxicity and Parkinson's Disease: Search for Neuroprotective Therapy
Volume: 16
Issue: 7
Author(s): Upasana Ganguly, Sankha Shubhra Chakrabarti, Upinder Kaur, Anwesha Mukherjee and Sasanka Chakrabarti*
Affiliation:
- Department of Biochemistry, ICARE Institute of Medical Sciences and Research, Haldia,India
Keywords:
α-Synuclein, autophagy, proteasomal degradation, mitochondrial dysfunction, chaperone, endoplasmic reticulum
stress, Parkinson's disease, microRNA, neuroprotective therapy.
Abstract: Background: There is a growing body of evidence in animal and cell based models of Parkinson's
disease (PD) to suggest that overexpression and / or abnormal accumulation and aggregation of
α-synuclein can trigger neuronal death. This important role of α-synuclein in PD pathogenesis is supported
by the fact that duplication, triplication and mutations of α-synuclein gene cause familial forms
of PD.
Methods: A review of literature was performed by searching PubMed and Google Scholar for relevant
articles highlighting the pathogenic role of α-synuclein and the potential therapeutic implications of
targeting various pathways related to this protein.
Results: The overexpression and accumulation of α-synuclein within neurons may involve both transcriptional
and post-transcriptional mechanisms including a decreased degradation of the protein
through proteasomal or autophagic processes. The mechanisms of monomeric α-synuclein aggregating
to oligomers and fibrils have been investigated intensively, but it is still not certain which form of this
natively unfolded protein is responsible for toxicity. Likewise the proteotoxic pathways induced by α-
synuclein leading to neuronal death are not elucidated completely but mitochondrial dysfunction, endoplasmic
reticulum (ER) stress and altered ER-golgi transport may play crucial roles in this process.
At the molecular level, the ability of α-synuclein to form pores in biomembranes or to interact with
specific proteins of the cell organelles and the cytosol could be determining factors in the toxicity of
this protein.
Conclusion: Despite many limitations in our present knowledge of physiological and pathological
functions of α-synuclein, it appears that this protein may be a target for the development of neuroprotective
drugs against PD. This review has discussed many such potential drugs which prevent the expression,
accumulation and aggregation of α-synuclein or its interactions with mitochondria or ER and
thereby effectively abolish α-synuclein mediated toxicity in different experimental models.
