KEY WORDS: neurodegenerative disease, SCA3, spinocerebellar ataxia 3, ataxin-3, ATXN3, SCA3 mouse, knock-in, mutant protein, PolyQ, CAG repeats, autophagy, proteasome
Principal Investigator: Maciej Figiel
Research topic: Investigation of a new therapeutic strategy to lower mutant protein in SCA3 / MJD
I. Project description
Neurodegenerative diseases, including polyglutamine diseases and Alzheimer's disease, are currently incurable. A model disease in this group is spinocerebellar ataxia type 3 (SCA3), which is a genetic neurodegenerative disease caused by a particular type of mutation that results in an increased number of CAG nucleotide repeats in the ATXN3 gene sequence. The mutation in the ATXN3 gene results in the defective protein ataxin-3, which forms toxic aggregates in the cell and also increases the cellular level of beta-amyloid. Ataxin-3 plays a crucial role in controlling which proteins and organelles should be cleared in the cell through two related cellular mechanisms called autophagy and UPS. Ataxin-3 recognizes a protein tag called ubiquitin that directs a protein or cell fragment for breakdown, and detaches this tag from the protein, thereby preventing premature removal of the proteins from the cell. In this project, we will investigate whether forcing the controlled removal of cell fragments by small molecule drugs will repair the disrupted cellular processes resulting from the ATXN3 mutation.
We hope that thanks to this project, we will learn more about the specific role of one of the key pathogenic processes in neurodegenerative diseases related to the dysfunction of protein clearance mechanisms. A detailed study of this mechanism will provide a better understanding of SCA3 and other neurodegenerative diseases, which will enable the design of appropriate treatments.
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