DJ-1 deficiency perturbs microtubule dynamics and impairs striatal neurite outgrowth

Abstract

Parkinson's disease (PD) is a common neurodegenerative disease characterized by the selective loss of the dopaminergic (DA) neurons in substantia nigra. The degeneration leads to decreased levels of DA in striatum and causes uncontrolled firing of innervated medium spiny neurons (MSNs), thus preventing the patient to act smoothly. Gene-specific deficient mouse models for the recessive forms of PD were generated in the past decade, although most failed to exhibit degeneration of DA neurons or decreased DA level, as evidenced in PD patients. Here by using DJ-1-knockdown neuroblastoma SH-SY5Y cells and Neuro-2a cells as well as DJ-1-deficient mice, we found DJ-1 deficiency could downregulate β-tubulin III via a hypoxia-inducible factor 1α (HIF-1α) pathway, and, correspondingly, we observed reduced microtubule dynamics. With Golgi-Cox impregnation, we also observed declined dendritic complexity and the loss of dendritic spines in striatal MSNs of DJ-1-deficient mice. Our results revealed a novel role of DJ-1 in the regulation of microtubule dynamics and suggested that striatal impairments may also play an important role as loss of DA neurons in the pathogenesis of PD.