Mayo Clinic Jacksonville has received a USD 1.87 million NIH RF1 grant from the National Institute of Neurological Disorders and Stroke to investigate whether amplifying PINK1 kinase activity can protect neurons against alpha-synuclein pathology — a central mechanism in Parkinson's disease and related Lewy body disorders.
The project, led by co-investigators Wolfdieter Springer and Pamela J. McLean, centers on a recently identified PINK1 gain-of-function variant — PINK1^G411A — that produces elevated ubiquitin kinase activity and accelerated mitophagy, the selective degradation of damaged mitochondria. Rather than compensating for PINK1 loss, as most prior research has attempted, the team is asking whether pushing PINK1 activity above baseline can confer neuronal resilience against alpha-synuclein (aSYN) toxicity and aggregation.
The rationale is mechanistically grounded: PINK1 and its E3 ligase partner Parkin cooperate to flag and clear dysfunctional mitochondria. Loss-of-function mutations in either gene are the predominant cause of early-onset familial Parkinson's disease. Separately, missense mutations or overexpression of SNCA — encoding aSYN — drive protein aggregation into Lewy bodies, the pathological hallmark of Parkinson's and Lewy body dementia. The two pathways have long been suspected to interact, but the nature and extent of that crosstalk remains poorly defined. This grant funds a direct experimental test of whether enhanced mitophagy can interrupt or attenuate aSYN-driven neurodegeneration.
The team will evaluate the PINK1^G411A variant across complementary model systems: iPSC-derived neurons and in vivo mouse brain, using both viral aSYN overexpression and exposure to patient-derived pathological aSYN seeds. The use of brain-derived seeds from Parkinson's patients adds translational weight, moving beyond synthetic or recombinant protein models toward material that more faithfully reflects disease-stage pathology.