Parkinson’s disease (PD) and Lewy body dementia (LBD) manifest pathological deposition of misfolded a-
synuclein (aSyn). Concerning LBD diagnoses, dementia with Lewy bodies (DLB) patients may show cognitive
decline and dementia from the onset of the disease, while other patients, initially diagnosed as PD with motor
symptoms, later progress to PD with dementia (PDD). However, there are no specific biomarkers to identify
patients at risk for PD or LBD prior to the appearance of clinical symptoms, or to objectively monitor motor- or
non-motor (e.g., dementia and depression) burdens to assess disease severity and progression. Moreover,
significant overlaps in clinical and neuropathological characteristics between Alzheimer’s disease (AD) and
LBD can make differential diagnosis of these conditions in some cases particularly challenging during life. In
PD, LBD and AD, synaptic injury and neuronal damage result at least in part from excessive generation of
reactive oxygen and nitrogen species (ROS/RNS) engendered by toxic forms of oligomeric aSyn or Aß. We
previously demonstrated that RNS can trigger aberrant protein S-nitrosylation (SNO-protein formation),
resulting in synaptic/neuronal damage. Our data provide evidence that S-nitrosylation of Parkin, PINK1, DJ-1,
and Uch-L1 each plays a causative role in disease-related neuronal damage in sporadic human PD and LBD.
Specifically, we demonstrate that prevention of aberrant protein S-nitrosylation ameliorates mitochondrial
dysfunction, protein misfolding, synaptic damage, and neuronal loss in both cell-based and animal models
manifesting misfolded aSyn or Aß. Moreover, we recently found significantly elevated levels of SNO-proteins,
including SNO-DJ-1 and SNO-UchL1, in CSF and serum of patients with PD and LBD synucleinopathies.
Hence, here we propose to establish SNO-Proteins as potential biomarkers in biofluids (i.e., CSF and serum),
serving as indicators of disease diagnosis, progression, and severity to PD/LBD. We will employ unbiased
screening approaches as well as previously identified SNO-proteins to develop biochemical biomarkers for
PD/LBD, distinguishable from AD. Upon successful completion of the proposed studies, we will establish a
clear Context-of-Use (COU) for a diagnostic/prognostic biomarker with SNO-proteins to support enrichment of
PD and LBD clinical study/trial populations; thus, these SNO biomarkers and their detailed methods of
detection will be ready to enter the next phase (i.e., analytical validation) of the biomarker development
process. Accordingly, we will identify novel SNO-proteins in patient serum and CSF using proteomics
approaches (R61/Aim #1), develop ELISA-based assays for these SNO-proteins (R61/Aim #2), and examine if
SNO-proteins can serve as potential diagnostic or prognostic biomarkers for PD/LBD using serum and CSF
obtained from human patients (R61/Aim #3 and R33/Aim#4).