The disease-associated alpha-synuclein (?SynD) that accumulates and deposits as misfolded protein aggregates in the brain is the pathological hallmark of Parkinson disease (PD), and also of other synucleinopathies causing non-PD parkinsonism such as multiple system atrophy (MSA) and dementia with Lewy bodies (DLB). Currently, a definitive diagnosis of these disorders often requires the detection of ?SynD in autopsy brain samples. An unmet medical need for PD and non-PD parkinsonism is to identify biomarkers for diagnosis, defining disease severity, and assessing potential neuroprotective therapeutics in easily accessible specimens. Notably, aSynD has been observed in the skin of PD patients by immunohistochemistry or immunofl3`2uorescence microscopy whereas the sensitivity varied dramatically from 0-100%. Remarkably, using the ultrasensitive assay termed real-time quaking-induced conversion (RT-QuIC), our recent preliminary studies have shown that the ?SynD-specific seeding activity is readily detectable in autopsy skin tissues of PD patients with 100% specificity and sensitivity. Moreover, the protein misfolding cyclic amplification (PMCA), another highly sensitive assay that detects ?SynD seeding activity even in formaldehyde-fixed brain tissue of a MSA patient, is also able to detect skin ?SynD seeding activity in PD patients but not in non-PD controls. We hypothesize that RT-QuIC and PMCA are highly sensitive and robust platforms to establish skin ?SynD as a biomarker for postmortem and premortem diagnoses of PD. To test this hypothesis, the following three Aims will be pursued: (1) to establish skin aSynD as a biomarker for postmortem diagnosis of PD; (2) Assess skin SynD as a biomarker for premortem diagnosis and defining PD severity using RT-QuIC and PMCA; and (3) Determine skin ?SynD as a biomarker for diagnosis of non-PD synucleinopathies such as MSA and DLB as well as differentiate synucleinopathies from tauopathies such as corticobasal degeneration and progressive supranuclear palsy. We believe that new knowledge generated from this study will further apply to other neurodegenerative diseases including the most common neurodegenerative disease Alzheimer's disease, where the disease-specific misfolded proteins such as tau protein and A? peptides have been also found in the skin of affected patients.

Public Health Relevance

Our recent studies indicate that skin samples of patients with Creutzfeldt-Jakob disease, a neurodegenerative disease associated with the deposition of a misfolded protein aggregate (PrPSc), exhibit detectable PrPSc. The aim of our proposal is to extend our preliminary findings that skin tissues also contain the misfolded ?- synuclein protein (?SynD) associated with Parkinson's disease (PD), the second most common neurodegenerative disease to address a critical issue whether the skin ?SynD can be a biomarker for premortem and postmortem diagnostic tests for PD. We expect that our study will not only provide insights into PD but also other common neurodegenerative diseases such as Alzheimer's disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZNS1)
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Babcock, Debra J
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Case Western Reserve University
Schools of Medicine
United States
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