Assessing skin biomarkers for preclinical diagnosis of PD and non-PD Parkinsonism

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ABSTRACT The disease-associated alpha-synuclein (αSynD) 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 αSynD 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 αSynD-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 αSynD seeding activity even in formaldehyde-fixed brain tissue of a MSA patient, is also able to detect skin αSynD 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 αSynD 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 αSynD 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 Aβ peptides have been also found in the skin of affected patients.