Expansion of trinucleotide repeat CAG, encoding glutamine, results in at least six progressive neurodegeneratie disorders. The normal functions of the gene products are largely unknown, but three features are apparent: (1) the polyglutamine region is the only sequence homology among the polyglutamine proteins; (2) polyglutamine proteins cause a common progressive neurodegenerate pathology and; (3)particular but different brain regions are affected in each disorder despite ubiquitous expression. Thus, key questions are how the polyglutamine proteins cause a common phenotype and what properties limit neuronal death to a specific region. Many hypotheses on the mechanism of polyglutamine disease such as excitotoxicity, altered energy metabolism and oxidative stress, do not address the regional component of neuronal death. We propose that the expanded glutamine region imparts new interactive properties. This mechanism satisfies both the neuronal targeting ia interactions of the common glutamine region and the regional targeting ia altered interactions of the unique flanking sequences. We will determine whether alterations in protein interactions of a representative polyglutamine protein, huntingtin, is relevant to human disease by analyzing self- (aggregation) and hetero- associations in relevant brain regions from human sources. By analyzing a second representative protein, ataxin-1, for which an excellent mouse model exists, we will determine whether common interactions occur, and how age, region, subcellular localization, and ataxin-1 turnover rate influence ataxin-1 interactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NS010562-01
Application #
2522701
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (01))
Project Start
1998-03-01
Project End
Budget Start
1997-09-08
Budget End
1998-09-07
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905