Parkinson’s disease (PD) is a debilitating
movement disorder characterised by the loss of dopaminergic neurons in the substantia nigra. As
neuroprotective agents mitigating the rate of neurodegeneration are unavailable, the current
therapies largely focus only on symptomatic relief. Here, we identified stress-inducible
phosphoprotein 1 (STIP1) as a putative neuroprotective factor targeted by PD-specific
autoantibodies. STIP1 is a co-chaperone with reported neuroprotective capacities in mouse Alzheimer’s disease and
stroke models. With human dopaminergic neurons derived from induced pluripotent stem cells, STIP1 was found to alleviate
staurosporine-induced neurotoxicity. A case-control study involving 50 PD patients (average age = 62.94 ± 8.48, Hoehn and Yahr >2 = 55%) and 50 age-matched healthy controls (HCs) (average age = 63.1 ± 8) further revealed high levels of STIP1
autoantibodies in 20% of PD patients compared to 10% of HCs. Using an overlapping
peptide library covering the STIP1
protein, we identified four PD-specific
B cell epitopes that were not recognised in HCs. All of these
epitopes were located within regions crucial for STIP1’s chaperone function or
prion protein association. Our clinical and neuro-immunological studies highlight the potential of the STIP1 co-chaperone as an endogenous
neuroprotective agent in PD and suggest the possible involvement of autoimmune mechanisms via the production of
autoantibodies in a subset of individuals.