|Ph.D Student||Eyal Allon|
|Subject||Characterization of Synphilin-1 Isoforms and Their Role in|
|Department||Department of Medicine||Supervisor||Professor Simone Engelender|
|Full Thesis text|
α-Synucleinopathies is a group of neurodegenerative disorders that are characterized by the presence of the α-synuclein protein in aggregates that are found in surviving neurons that belong to the affected neuronal population. The most common disease from this group is Parkinson's disease, in which α-synuclein is present in Lewy bodies, which are the intracellular aggregates characteristically found in the dopaminergic neurons affected in this disorder.
In order to gain further insights into the pathogenesis of α-synucleinopathies and the role of aggregate formation in their development, we decided to study the role of synphilin-1, an α-synuclein-interacting partner, in these processes. During our study, we identified a new synphilin-1 isoform, which we have termed synphilin-1A. Synphilin-1A is translated from a transcript that differs in its exonic content from that of synphilin-1 and, most interestingly, utilizes a different reading frame for its translation. This is the first time that usage of alternative reading frames of transcripts originating from the same gene has been demonstrated and, if this unique mode of translation also occurs in other genes, it may greatly enhance the repertoire of proteins that can been generated from the fixed amount of genes found in our genome.
We found that synphilin-1A and α-synuclein interact with each other and that these two proteins are co-localized in inclusions formed in neurons grown in primary cultures. In addition, synphilin-1A is present in Lewy bodies of Parkinson's disease patients and also accumulates in an aggregated form in brain tissue of patients with Diffuse Lewy body disease, which is another neurodegenerative disorder from the group of α-synucleinopathies. These findings imply a possible connection between synphilin-1A and α-synucleinopathies.
Over-expression of synphilin-1A, but not synphilin-1, in neurons caused increased toxicity and cell death, both of which were markedly attenuated by the sequestration of synphilin-1A in intracellular inclusions. We found that the formation of synphilin-1A-containing inclusions can be driven by inhibition of the proteasome and also, possibly, by changing the ratio between the amounts of synphilin-1 and SIAH-1, an E3 ubiquitin ligase previously linked to synphilin-1, with an increased ratio driving formation of inclusions.
Taken together, these findings strongly imply a role for synphilin-1A in the pathogenesis of α-synucleinopathies and also provide some insights regarding inclusion bodies, their role in neurodegenerative disorders and their mode of formation. We strongly believe that the future study of synphilin-1A will greatly enhance our understanding of these disorders.