Novel chaperones and neurodegeneration

NIH RePORTER · NIH · R01 · $26,037 · view on reporter.nih.gov ↗

Abstract

Abstract The polyglutamine diseases are a class of nine neurodegenerative diseases caused by the expansion of a CAG trinucleotide repeat in the coding region of specific genes. Translation of these expanded CAG repeats results in the production of a protein with an expanded polyglutamine tract. Proteins with these expanded polyglutamine tracts aggregate and result in neuronal toxicity. Therefore, the identification of factors that suppress polyglutamine aggregation may lead to the development of therapies for the polyglutamine diseases. In most model organisms expression of a polyglutamine repeat results in aggregation, however, we have found that the social amoeba Dictyostelium discoideum naturally expresses thousands of polyglutamine repeats that remain soluble. Furthermore, we and others have found that expression of a polyglutamine expanded huntingtin exon 1 construct (mHtt) that aggregates in other model organisms remains soluble in Dictyostelium. This has led us to hypothesize that Dictyostelium encodes for novel proteins and/or pathways that suppresses polyglutamine aggregation. To identify factors that suppress polyglutamine aggregation we have carried out a screen and identified a single gene that suppresses polyglutamine aggregation in Dictyostelium. One caveat to this screen was that it was labor intensive and only covered less than five percent of the genome. To overcome this limitation Ms. Felicia Williams has established a new screening protocol that will allow near genome-wide saturation. She will learn new methodology, gain technical expertise, publish high impact research, and prepare herself to obtain a postdoctoral fellowship. Overall this project will complement the parental grant and ongoing experiments in the lab to identify novel mechanisms to suppress polyglutamine aggregation and determine if these mechanisms can be translated into therapies.

Key facts

NIH application ID
10525677
Project number
3R01NS112191-03S1
Recipient
DUKE UNIVERSITY
Principal Investigator
Kenneth Matthew Scaglione
Activity code
R01
Funding institute
NIH
Fiscal year
2022
Award amount
$26,037
Award type
3
Project period
2019-07-01 → 2024-04-30