High molecular weight insoluble parkin in the substantia nigra of patients with idiopathic Parkinson’s disease

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Abstract Parkinson’s disease (PD) is characterized by a loss of dopaminergic neurons and accumulation of α-synuclein (α-syn)-containing Lewy bodies in the substantia nigra (SN) pars compacta. Mutations in the gene coding for the protein parkin cause a form of autosomal recessive juvenile parkinsonism, but its role in idiopathic PD is poorly understood. Here, to investigate parkin changes in the SN in PD, we established a clinicopathology research platform comparing PD patients (n = 24) with Controls (n = 21). We first confirmed the massive loss of dopamine (DA) levels (-96%) in the putamen of PD patients, using HPLC/electrochemistry. Higher levels of phosphorylated α-syn (αsynP129) (23-fold) were observed in the SN of PD patients by Western immunoblotting. In formic acid extracts, an increase in the insoluble oligomeric form of parkin migrating at 260 kDa was observed (+ 49%) in the SN of PD patients, along with lower levels of the 55 kDa monomeric form (-47%). These changes in parkin were specific for the SN, and not observed in the putamen, parietal cortex and cerebellum. High molecular weight parkin correlated with αsynP129 levels and dopamine loss and was more prominently found in PD patients with levodopa-induced dyskinesias. Additional studies in animal models suggest that the aggregation of parkin is not a direct consequence of dopaminergic depletion or αsyn overproduction, but a component of PD cellular pathophysiology. Taken together, the results reported herein show that, beside dopamine loss and increased αsynP129, neurodegeneration in idiopathic PD is associated with a conversion of parkin into an insoluble high molecular weight form in the SN.

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