Huntington's disease causes motor and cognitive dysfunctions, the degeneration of striatal and cortical neurons in the brain, and death of its victim within 15-20 years. The genetic mutation is an expanded region of polyglutamines at the N-terminus of huntingtin. The function of wild-type huntingtin and the mechanism of HD pathogenesis caused by mutant huntingtin are unknown. We have observed an abnormal accumulation and transport of huntintin in affected neurons of the HD brain. Similar patterns of mutant huntintin accumulation appear in clonal striatal cells transfected with cDNAs encoding huntingtin with an expanded polyglutamine region. Published studies and our preliminary observations suggest that wild-type huntingtin may function in receptor- mediated endocytosis. Mutant huntintin, like wild-type huntingtin, associates with clathrin-enriched membranes. Our overall hypothesis is that mutant huntintin causes neuronal dysfunction through its direct effects on receptor-mediated endocytosis and by its abnormal accumulation and transport. We propose a series of studies in clonal striatal cells to explore wild-type huntingtin's association with endosomes (Aimsl), to analyze the consequences of polyglutamine expansion in huntintin on endocytic function (Aim 2), and to evaluate the subcellular compartments that accumulate mutant huntingtin and contribute to cell death (Aim 3). Our studies will include techniques in confocal immunofluorescence microscopy, immunogold/electron microscopy, subcellular membrane fractionation, immunoisolation and Western blot. The results will identify the subcellular processes involved in HD pathogenesis and will lead to a rational strategy for treatment of this devastating disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS035711-02S1
Application #
6095815
Study Section
Neurology A Study Section (NEUA)
Program Officer
Oliver, Eugene J
Project Start
1998-08-15
Project End
2002-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
McClory, Hollis; Wang, Xiaolong; Sapp, Ellen et al. (2018) The COOH-terminal domain of huntingtin interacts with RhoGEF kalirin and modulates cell survival. Sci Rep 8:8000
Valencia, Antonio; Reeves, Patrick B; Sapp, Ellen et al. (2010) Mutant huntingtin and glycogen synthase kinase 3-beta accumulate in neuronal lipid rafts of a presymptomatic knock-in mouse model of Huntington's disease. J Neurosci Res 88:179-90
Li, Xueyi; Sapp, Ellen; Chase, Kathryn et al. (2009) Disruption of Rab11 activity in a knock-in mouse model of Huntington's disease. Neurobiol Dis 36:374-83
Kim, Yun J; Sapp, Ellen; Cuiffo, Benjamin G et al. (2006) Lysosomal proteases are involved in generation of N-terminal huntingtin fragments. Neurobiol Dis 22:346-56
Kegel, Kimberly B; Sapp, Ellen; Yoder, Jennifer et al. (2005) Huntingtin associates with acidic phospholipids at the plasma membrane. J Biol Chem 280:36464-73
Rubinsztein, David C; DiFiglia, Marian; Heintz, Nathaniel et al. (2005) Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy 1:11-22
Kim, Manho; Roh, Jae-Kyu; Yoon, Byung Woo et al. (2003) Huntingtin is degraded to small fragments by calpain after ischemic injury. Exp Neurol 183:109-15
Kegel, Kimberly B; Meloni, Alison R; Yi, Yong et al. (2002) Huntingtin is present in the nucleus, interacts with the transcriptional corepressor C-terminal binding protein, and represses transcription. J Biol Chem 277:7466-76
Petersen, A; Chase, K; Puschban, Z et al. (2002) Maintenance of susceptibility to neurodegeneration following intrastriatal injections of quinolinic acid in a new transgenic mouse model of Huntington's disease. Exp Neurol 175:297-300
Chan, Edmond Y W; Luthi-Carter, Ruth; Strand, Andrew et al. (2002) Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington's disease. Hum Mol Genet 11:1939-51

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