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Diabetic neuropathy develops on a background of hyperglycemia and an entangled metabolic imbalance. There is increasing evidence of central nervous system involvement in diabetic neuropathy and no satisfactory treatment except maintenance of good glycemic control, thereby highlighting the importance of identifying novel therapeutic targets. Purkinje cells are a class of metabolically specialized active neurons, and degeneration of Purkinje cells is a common feature of inherited ataxias in humans and mice. However, whether Purkinje cells are implicated in diabetic neuropathy development under metabolic stress remains poorly defined. Here, we revealed a novel leucine-rich repeat kinase 2 (LRRK2)-mediated pathway in Purkinje cells that is involved in the pathogenesis of diabetic neuropathy from a 24-week long study of streptozotocin (STZ)-diabetic rats. We found that hyperglycemia, cerebellum proinflammatory cytokines, and chemokines increased markedly in 24-week STZ-diabetic rats. Furthermore, we demonstrated that degeneration of Purkinje cells is characterized by progressive swellings of axon terminals, no autophagosome formation, the reduction of LC3II/LC3I and Lamp2, and accumulation of p62 puncta in 24-week STZ-diabetic rats. Importantly, a higher expression level of LRRK2-mediated hyperphosphorylation of tau along with increased mitochondrial dynamin-like protein (mito-DLP1) was demonstrated in 24-week STZ-diabetic rats. This effect of LRRK2 overexpression induced mitochondrial fragmentation, and reduced mitochondrial protein degradation rates were confirmed in vitro. As a consequence, 24-week STZ-diabetic rats showed mitochondrial dysfunction in cerebellar Purkinje neurons and coordinated motor deficits evaluated by rotarod test. Our findings are to our knowledge the first to suggest that the LRRK2-mediated pathway induces mitochondrial dysfunction and loss of cerebellar Purkinje neurons and, subsequently, may be associated with motor coordination deficits in STZ-diabetic rats. These data may indicate a novel cellular therapeutic target for diabetic neuropathy.

cell death and disease

Mitochondrial dysfunction driven by the LRRK2-mediated pathway is associated with loss of Purkinje cells and motor coordination deficits in diabetic rat model