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.
| Hinkle, Jared Thomas; Perepezko, Kate; Bakker, Catherine C et al. (2018) Onset and Remission of Psychosis in Parkinson's Disease: Pharmacologic and Motoric Markers. Mov Disord Clin Pract 5:31-38 |
| Kam, Tae-In; Mao, Xiaobo; Park, Hyejin et al. (2018) Poly(ADP-ribose) drives pathologic ?-synuclein neurodegeneration in Parkinson's disease. Science 362: |
| Sathe, Gajanan; Na, Chan Hyun; Renuse, Santosh et al. (2018) Phosphotyrosine profiling of human cerebrospinal fluid. Clin Proteomics 15:29 |
| 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 |
| Hinkle, Jared T; Perepezko, Kate; Bakker, Catherine C et al. (2018) Domain-specific cognitive impairment in non-demented Parkinson's disease psychosis. Int J Geriatr Psychiatry 33:e131-e139 |
| Hinkle, Jared T; Perepezko, Kate; Mills, Kelly A et al. (2018) Dopamine transporter availability reflects gastrointestinal dysautonomia in early Parkinson disease. Parkinsonism Relat Disord 55:8-14 |
| Kim, Donghoon; Hwang, Heehong; Choi, Seulah et al. (2018) D409H GBA1 mutation accelerates the progression of pathology in A53T ?-synuclein transgenic mouse model. Acta Neuropathol Commun 6:32 |
| 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 |
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