Huntingtin associated protein-1 (HAP1) is enriched in neurons and is found to be involved in intracellular trafficking. The role of HAP1 in intracellular trafficking is supported by its interactions with a number of proteins including dynactin p150 and kinesin, which are involved in microtubule-dependent transport. Recent studies also suggest that HAP1 participates in vesicular trafficking and endocytosis of membrane receptors. The crucial function of HAP1 was further demonstrated by HAP1 knockout mice that are pbstnatally lethal and show neurodegeneration in the brain. These interesting findings raise more questions about how HAP1 is involved in the complex intracellular trafficking in neurons. Our recent studies show that HAP1 interacts with 14-3-3 and that this interaction is regulated by phosphorylation of HAP1. We hypothesize that HAP1 may link specific cargos to the microtubule transporters and that it's interactions with partners are regulated by its posttranslational modifications. Such regulation allows HAP1 to participate in intracellular transport of various cargos and endocytosis of membrane receptors. Given the idea that HAP1 dysfunction may be involved in HD pathology, it is also important to investigate if the loss of HAP1 can affect its function in intracellular trafficking. Accordingly, we propose three aims in this application.
In Aim 1, we will investigate whether 14-3-3 and phosphorylation regulate the interactions of HAP1 with microtubule transporters dynactin p150and kinesin.
In Aim -2, we will use HAP1 knockout mice and siRNA approaches to examine whether decreasing MAPI's expression alters microtubule-dependent transport and neuronal function in different types of neurons.
In Aim -3, we will study whether HAP1 deficiency affects endocytosis of membrane receptors and whether defective HAP1-associated endocytosis contributes to HD pathology. These studies aim to elucidate the function of HAP1 and to help understand the mechanisms for intracellular trafficking in neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036232-11
Application #
7743722
Study Section
Neural Degenerative Disorders and Glial Biology Study Section (NDGB)
Program Officer
Sutherland, Margaret L
Project Start
1998-01-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
11
Fiscal Year
2010
Total Cost
$331,341
Indirect Cost
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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