A polygutamine expansion in the N-terminus of huntingtin (N-hn) causes Huntington's disease (HD). There is no effective treatment for HD. Although mutant N-Fin fragments are known to accumulate in HD neurons and cause cell dysfunction in vitro, a mechanism (or mechanisms) that explains the selective loss of striatal and cortical projection neurons remains elusive. Wild type and mutant htt associate with membranes in the endocytic and secretory pathway. Our overall hypothesis is that mutant N-htt 's association with neuronal membranes contributes to early cellular dysfunction in the cytoplasm in HD. One of these membrane compartments includes the autophagosome/lysosomal system, which accumulates full-length or large N-htt fragments of mutant htt. Although htt ostensibly lacks transmembrane domains, it associates tightly with membranes. We speculate that candidate domains in the N-terminus involved in protein-protein interactions promote membrane binding. Little is known about the degradative pathways that form N-htt fragments in vivo. Identifying the sites of protease cleavage in the N-terminus of htt is important for understanding how the protein is regulated. Calpain, a calcium dependent protease, which regulates the function of many proteins involved in membrane/cytoskeleton organization, cleaves htt near its N-terminus and produces long-lived N-htt fragments that are enriched in membrane fractions in brain. We speculate that mutant N-htt products of calpain cleavage undergo a different processing from the wt fragments in neurons that leads to cellular dysfunction in HD. HD mice also show abnormal function of striatal NMDA receptors. One way that mutant Fin might cause the dysfunction of NMDA receptors is by disrupting the assembly of NMDA receptor subtypes at the cell surface.
The specific aims are: 1: To understand the role of mutant htt induced autophagy in cell dysfunction, 2: To determine whether htt proteolysis by calpain contributes to HD pathogenesis and 3: To determine the effects of mutant htt on protein transport within the secretory pathway. The results of these studies will provide new insights about the mechanisms of cellular dysfunction in HD and suggest novel therapeutic targets that can reduce the potentially harmful effects of mutant N-htt fragments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035711-08
Application #
6927160
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Sutherland, Margaret L
Project Start
1998-08-15
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2007-07-31
Support Year
8
Fiscal Year
2005
Total Cost
$629,752
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
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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