To understand how the microtubule motors, cytoplasmic dynein and kinesins, find and transport cargoes to specific cellular destinations, we need to know much more about how motors are attached to cargoes. The extended morphology of axons and dendrites makes post-mitotic neurons especially dependent on polarized transport and ideal for studying the regulation of transport. We recently showed that ss-spectrin mutations in humans that cause spinocerebellar ataxia type 5 (SCA5) impair motor-based transport of synaptic vesicles in a Drosophila model of neurodegeneration. In this application, we focus on an analysis of ss-spectrin and its role in mediating the attachment of dynactin and cytoplasmic dynein to cargoes in neurons. We will characterize the defective neuronal transport in our fly model and will pursue the gene products and mechanisms that regulate transport. The selective use of the proposed spectrin/ motor linkage in will be studied in the axons and dendrites of living neurons (Aim 1). New genetic modifiers of the SCA5 phenotypes and neuronal transport will be characterized in motility and biochemical assays (Aim 2), and the connection between neuronal transport, autophagy and neurodegeneration will be explored (Aim 3). Our work has important long-term implications for the understanding and treatment of spinal cord injuries, and the family of neurodegenerative diseases, including Amyotrophic lateral sclerosis, Huntington's Disease, and Alzheimer's Disease.

Public Health Relevance

We are studying the molecular basis of intracellular transport. Our work focuses on the microtubule motors cytoplasmic dynein and kinesin and their function in neurons. We have developed a fly model for neurodegeneration in the disease Spinocerebellar ataxia type 5 and we will study how perturbations in intracellular transport contribute to neurodegenerative disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM044757-21
Application #
8280349
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Gindhart, Joseph G
Project Start
1990-07-01
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
21
Fiscal Year
2012
Total Cost
$333,929
Indirect Cost
$112,784
Name
University of Minnesota Twin Cities
Department
Genetics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Boylan, Kristin L M; Mische, Sarah; Li, Mingang et al. (2008) Motility screen identifies Drosophila IGF-II mRNA-binding protein--zipcode-binding protein acting in oogenesis and synaptogenesis. PLoS Genet 4:e36
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