The present proposal aims at examining the age-dependent impairment of proteasome function in Huntington's disease (HD). HD is caused by a polyglutamine expansion in the NH2-terminal region of huntingtin (htt). The toxicity of mutant N-terminal htt is indicated by its ability to misfold, aggregate and form intranuclear inclusions. We have found that accumulation of mutant htt fragments are associated with an age-dependent decrease in proteasome activity. This suggests that age-dependent decrease of proteasomal function reduces the ability of neurons to remove toxic N-terminal htt fragments and leads to their accumulation. To study whether the decreased proteasome activity is associated with preferential accumulation of N-terminal htt fragments in the straitum and cortex of HD repeat knockin mice (Kl) we are using a construct encoding a green fluorescent protein (GFP) reporter carrying a constitutively active degradation signal to study the relationship between the activity of the ubiquitin proteasome system (UPS) and htt aggregation. The reporter (GFPu) will be inserted into an adenoviral vector for sterotaxic injections into Kl mice brains to determine how proteasome function is associated with aging, htt aggregation and neurotoxicity in different brain regions. The relevance of this research to public health is to address the late onset of Huntington's disease (HD). If we had a better understanding of the impact aging and mutant N-terminal htt has on proteasome function then it could serve as a possible thearpeutic target for HD. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AG026804-02
Application #
7362422
Study Section
Special Emphasis Panel (ZRG1-GGG-T (29))
Program Officer
Wise, Bradley C
Project Start
2007-02-01
Project End
2009-01-18
Budget Start
2008-02-01
Budget End
2009-01-18
Support Year
2
Fiscal Year
2008
Total Cost
$27,615
Indirect Cost
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322