Abstract

The pathogenesis of Parkinson's Disease (PD) involves death of dopaminergic neurons in the substantia nigra and Lewy bodies in the substantia nigra and other brain regions, including brainstem monominergic neurons, and neurons in the cerebral cortex. Alpha-Synuclein mutations cause autosomal dominant forms of PD clinically indistinguishable from sporadic PD. In addition, alpha-synuclein is a component of the Lewy bodies in both PD and in Diffuse Lewy Body disease.
In Specific Aim #1 we will identify protein interactors for alpha-synuclein using the yeast two- hybrid system and confirm the interactions using biochemical techniques.
In Specific Aim #2 we will characterize the cellular pattern of expression of these interactors in comparison with alpha-synuclein.
In Specific Aim #3 we will make a cell model which reproduces some of the features of PD using transient and stable expression of alpha-synuclein and interacting proteins in cell culture. We will study the pathways of cell death which are activated in this model. Taken together these studies will shed light on the molecular and cellular pathogenesis of PD and provide models for testing of experimental therapeutics.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
1P50NS038377-01
Application #
6112674
Study Section
Project Start
1998-09-30
Project End
1999-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Type
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

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