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Sokol V. Todi, Ph.D.
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RESEARCH INTERESTS:
Molecular pathways involved in neurodegenerative diseases.
Age-related neurodegeneration, including Alzheimer's Disease, Parkinson's Disease and Polyglutamine Diseases (e.g. Huntington's Disease), afflicts millions of people worldwide. Our understanding of molecular mechanisms involved in each of these diseases is incomplete, and no cures exist for them. By using a combination of in vitro biochemistry, mammalian cell culture assays and fruit fly (Drosophila melanogaster) genetics, our new laboratory is involved in projects whose goal is to identify and characterize enzymes important for neuronal homeostasis and neurodegeneration:
1- Which Drosophila orthologues of human deubiquitinating enzymes are important for neuronal survival during proteotoxic stress? Deubiquitinating enzymes (DUbs) regulate many cellular pathways, from gene transcription to protein degradation. Through a targeted screen we aim to identify and to characterize biochemically DUbs that are crucial to neuronal homeostasis when challenged by toxic protein species.
2- How does ataxin-3 protect neurons from degeneration? Ataxin-3 is a DUb with both neuroprotective and neurodegenerative properties. When mutated, ataxin-3 causes neurodegeneration in Spinocerebellar Ataxia Type 3, perhaps the most common dominantly inherited ataxia in the world. Ataxin-3, however, also protects fly neurons from degenerating in the presence of toxic proteins. The mechanisms by which ataxin-3 protects neurons are unknown, and we are investigating these processes by using fly lines and mammalian cell cultures that express different forms of ataxin-3.
3- USP25: an ERAD DUb? ERAD (ER-Associated Degradation) is a basic cellular pathway that controls protein quality. According to our preliminary work, USP25 functions in ERAD, rescuing ERAD substrates from degradation. We are currently investigating the molecular partners of USP25 in ERAD and the molecular mechanism through which USP25 rescues ERAD substrates.
Selected Publications
Todi SV, Laco MN, Winborn BJ, Travis SM, Wen HM, Paulson HL (2007). Cellular turnover of the polyglutamine disease protein ataxin-3 is regulated by its catalytic activity. Journal of Biological Chemistry, Vol 282(40): 29348-58.
Winborn BJ, Travis SM, Todi SV, Scaglione KM, Xu P, Williams AJ, Cohen RE, Peng J, Paulson HL (2008). The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits K-63 linkages in mixed linkage ubiquitin chains. Journal of Biological Chemistry, Vol 283(39): 26436-43. (SVT: Conducted and analyzed all cell-based assays, conducted and analyzed some in vitro experiments, prepared figures).
Todi SV, Winborn BJ, Scaglione KM, Blount JR, Travis SM, Paulson HL (2009). Ubiquitination directly enhances activity of the deubiquitinating enzyme ataxin-3. The EMBO Journal, Vol 28(4): 372-82.
Nicastro G*, Todi SV*, Karaca E, Bonvin AMJJ, Paulson HL, Pastore A (2010). Understanding the role of the Josephin domain in the polyUb binding and cleavage properties of ataxin-3. PLoS ONE 5(8): e12430. doi:10.1371/journal.pone.0012430. * - equal contribution.
Todi SV, Blount JR, Scaglione KM, Basrur V, Conlon PK, Pastore A, Elenitoba-Johnson K, Paulson HL (2010). Activity and cellular functions of the deubiquitinating enzyme and polyglutamine disease protein ataxin-3 are regulated by ubiquitination at lysine 117. Journal of Biological Chemistry, Vol 285(50): 39303-13.
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