- PROJECT 3: ESTABLISHING CLINICAL UTILITY OF CSF BIOMARKERS FOR PD Accurate diagnosis of Parkinson's disease (PD) and monitoring of PD patients remain challenging and preclude the most effective patient care. Although the NINDS and other PD patient advocacy groups such as the Michael J. Fox Foundation have recognized the need for both diagnostic and prognostic PD biomarkers, no such biomarkers have been validated thus far. This Clinical Research Project will utilize Multiple Reaction Monitoring-Mass Spectrometry (MRM-MS) to determine if specific protein phosphorylation events can be used as novel PD-specific diagnostic/prognostic biomarkers. Previous research has shown that the non-receptor tyrosine kinase, c-Abl, phosphorylates ?Synuclein at the Y-39 site and Parkin at the Y-143 site. During PD, dysregulation of these two pathways ultimately leads to neuronal cell death, which in turn leads to the clinical manifestations of PD. In preliminary studies, we have already developed MRM-MS based quantitative assays to monitor these phosphorylated and unphosphorylated forms of ?-Synuclein and Parkin in CSF samples. Our hypothesis is that dysregulation of c- Abl signaling cascade is intrinsically linked to PD pathogenesis and that the relative phosphorylation state of downstream c-Abl substrates, ?-Synuclein and Parkin, should provide a sensitive read-out for the presence and/or the severity of PD.
Aim 1 will measure the relative concentration of the Y-39 tryptic peptide of ?-Synuclein in both its phosphorylated and unphosphorylated forms in the CSF of PD patients and controls. This assay will be employed in several clinical cohorts to determine whether the phosphorylated Y-39 residue can function as (i) a diagnostic marker by differentiating between PD patients and controls and/or (ii) a prognostic PD marker in patients that can be used for assessment of early and late (more severe) stages of PD.
Aim 2 will adopt the same approach as described in Aim 1 to test whether c-Abl mediated phosphorylation of Parkin at Y-143 can be used to facilitate either diagnosis with PD or patient monitoring as a function of disease severity. Taken together, this project will identify and validate c-Abl substrates as novel diagnostic/prognostic protein-based biomarkers that have the potential to provide clinicians with novel strategies for establishing a definitive diagnosis of PD and/or for monitoring the severity of disease in patients with PD.

Public Health Relevance

Currently, there is no clinical biomarker that has been approved for use in diagnosis or monitoring of Parkinson's Disease. The goal of this project is to use multiple reaction monitoring mass spectrometry (MRM- MS) to evaluateknown c-Abl substrates (phosphorylated Tyrosine-39 of alpha-synuclein and phosphorylated Tyrosine-143 of Parkin) as diagnostic/prognostic CSF-based biomarkers for PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
2P50NS038377-16
Application #
8882847
Study Section
Special Emphasis Panel (ZNS1-SRB-J (07))
Project Start
Project End
Budget Start
2014-09-30
Budget End
2015-07-31
Support Year
16
Fiscal Year
2014
Total Cost
$243,000
Indirect Cost
$93,000
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

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