Studies of the pathogenesis of familial PD will likely contribute to understanding the pathogenesis of all forms of PD. Familial PD can be caused by mutations in alpha-synuclein, parkin or DJ-1. We have identified synphilin-1 as an alpha-synuclein interacting protein, and found that it is a component of the ubiquitinated Lewy bodies in PD postmortem brain, and can be a substrate for ubiquitination by parkin. In a collaborative study, we have suggestive evidence that an R621C mutation in synphilin-1 may be a rare cause of PD. We have found that S 129 phosphorylation of alpha-synuclein strongly modulates inclusion formation in cell culture. We are developing inducible cell models of mutant alpha-synuclein toxicity, and have found that expression of A53T mutant alpha-synuclein causes direct cell toxicity. We propose to characterize the mechanisms of cell death caused by mutant alpha-synuclein, and the interactions of these proteins in the pathogenesis of PD.
In Specific Aim 1 we will study alpha-synuclein inducible PC 12 cell lines and mechanisms of cell toxicity, including the role of phosphorylation and cleavage of alpha-synuclein (in collaboration with Project 3), and possible modulation of toxicity by DJ-1 (in collaboration with Project 4).
In Specific Aim 2 we will characterize the interactions among alpha-synuclein, synphilin-1 and parkin (in collaboration with Project 1 and the Neuropathology Core). We hypothesize that inclusions are preferentially ubiquitinated via K63 linkage rather than K48 linkage, consistent with a potential role in cell signaling as well as protein degradation.
In Specific Aim 3 we will study the phosphorylation of alpha-synuclein, and determine whether phosphorylation modulates interactions with synphilin-1, and promotes aggregation or cleavage, in collaboration with Project 1 and 3, and the Neuropathology Core. Finally in Specific Aim 4 we will create synphilin-1 transgenic mice. We will cross them with mice overexpressing alpha-synuclein, and characterize their behavior and pathology, in collaboration with Project 3 and the Transgenic Mouse Core. We will also cross these double transgenic mice with parkin knockout mice. If this looks promising, we can generate mice overexpressing synphilin-1 with an R621C mutation which may be linked to PD, and characterize their phenotype. We will also generate mice overexpressing alpha-synuclein with the S129A mutation, and characterize their phenotype. These studies taken together should shed light on interactions among proteins implicated in PD, and on the mechanisms of PD pathogenesis. They are likely to lead to improved cell and mouse models of the disease, which will facilitate the search for rational therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS038377-09
Application #
7491150
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
9
Fiscal Year
2007
Total Cost
$387,056
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Guerreiro, Rita; Ross, Owen A; Kun-Rodrigues, Celia et al. (2018) Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol 17:64-74
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Kim, Sangjune; Yun, Seung Pil; Lee, Saebom et al. (2018) GBA1 deficiency negatively affects physiological ?-synuclein tetramers and related multimers. Proc Natl Acad Sci U S A 115:798-803
Kim, Donghoon; Yoo, Je Min; Hwang, Heehong et al. (2018) Graphene quantum dots prevent ?-synucleinopathy in Parkinson's disease. Nat Nanotechnol :
Hinkle, Jared T; Perepezko, Kate; Mari, Zoltan et al. (2018) Perceived Treatment Status of Fluctuations in Parkinson Disease Impacts Suicidality. Am J Geriatr Psychiatry 26:700-710
Kaji, Seiji; Maki, Takakuni; Kinoshita, Hisanori et al. (2018) Pathological Endogenous ?-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy. Stem Cell Reports 10:356-365

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