Mutations in the parkin gene are the main genetic cause of autosomal recessive Parkinson's disease (PD) and mutations in parkin also play a major role in familial PD. Preliminary studies indicate a potential pivotal role for parkin in the ubiquitin proteasomal pathway (UPP) by functioning as an ubiquitin E3 ligase. Most disease causing mutations of parkin are thought to be loss of function mutations that ultimately lead to the absence of ubiquitination and the subsequent failure of UPP-mediated degradation of parkin substrates. Thus, the abnormal accumulation of parkin substrates is thought to play a role in the demise of substantia nigra dopaminergic neurons in patients with parkin mutations. A number of putative parkin substrates have been identified, but their importance in the pathogenesis of PD due to parkin mutations is not known. We propose to characterize parkin knockout mice to formally test the hypothesis that the absence of parkin function is the cause of PD due to parkin mutations. Furthermore, biochemical and proteomic characterization of the parkin knockout mice may shed light on the substrates that are important in the pathogenesis of PD due to parkin mutations. Accordingly experiments are proposed to further characterize the role of parldn and it's substrates in the pathogenesis of PD.
In Specific Aim #1 we will characterize parkin knockout mice.
In Specific Aim #2 we will evaluate the sensitivity of parkin knockouts to environmental toxins.
In Specific Aim #3 we will evaluate the interaction of parkin with the alpha-synuclein interacting protein, synphilin-1 and determine whether parkin mediates K48 or K63 ubiquitin linkages.
In Specific Aim #4 we will determine whether parkin interacts with alpha-synuclein by evaluating of the effect of crossing parkin knockout mice with A53T mutant alpha-synuclein transgenic mice and further evaluate the interaction of parkin with the alpha-synuclein interacting protein, synphilin-1.
In Specific Aim #5 we will identify and characterize parkin interacting proteins and identify compensatory changes in parkin knockout mice. Development and characterization of parkin knockout, understanding the relationship of parkin, alpha-synuclein and synphilin- 1 in the pathogenesis of PD may provide insight into the molecular mechanisms by which these gene products induce neuronal damage and may provide novel therapeutics and targets to prevent the toxic effects of these familial associated genes in the degenerative process of PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS038377-07
Application #
7126031
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
7
Fiscal Year
2005
Total Cost
$331,550
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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
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

Showing the most recent 10 out of 250 publications