We will extend a line of investigation that suggests that "multiple hits", consisting of mishandling of 1) alphasynuclein (a-syn) degradation, 2) cytosolic calcium, and 3) cytosolic dopamine (DA), underlie Parkinson's disease (PD). Our preliminary results indicate that if any of these factors are absent in neuronal culture models of selective substantia nigra (SN) death, neurodegeneration can be blocked. During the prior Udall period, we 1) developed intracellular patch electrochemistry (IPE) to measure cytosolic dopamine (Mosharov et al., 2003;Mosharov et al., 2006b) and 2) reported that a-syn is specifically degraded within specialized lysosomes by chaperone-mediated autophagy (CMA), but that pathogenic a-syn mutants and DA-modified-a-syn (DA-syn) block CMA (Cuervo et al., 2004;Martinez-Vicente et al., 2008). In the current proposal, we characterize how a-syn is trafficked to lysosomes and blocks CMA (Aim 1) how cytosolic Ca++ controls cytosolic DA in SN neurons (Aim 2) and how the combination of these three "hits" disturbs normal homeostasis and may cause in pathology in mice (Aim 3).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS038370-15
Application #
8546445
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
15
Fiscal Year
2013
Total Cost
$355,094
Indirect Cost
$83,519
Name
Columbia University (N.Y.)
Department
Type
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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