Serum Response Factor Promotes Dopaminergic Neuron Survival via Activation of Beclin 1-Dependent Autophagy

Abstract

Serum response factor (SRF), a transcription factor highly expressed in neurons, is involved in neuronal survival and the pathogenesis of some neurodegenerative disorders. The ablation of SRF renders the midbrain dopaminergic (DA) neurons vulnerable to 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine-induced neurotoxicity, however, the underlying mechanisms remain poorly understood. Here, we report decreased SRF levels in the substantia nigra (SN) of rotenone-treated rats that was associated with the loss of tyrosine hydroxylase (TH)-positive neurons. SRF expression was also reduced in rotenone-treated PC12 cells in vitro. In addition, Srf knockdown augmented rotenone-induced toxicity in PC12 cells. In contrast, overexpression of Srf attenuated the cells' sensitivity to rotenone and alleviated rotenone-induced α-synuclein accumulation. The protective effect of SRF was abolished when the expression of autophagy-related proteins Beclin 1 and Atg5 was suppressed. These results suggested that SRF may promote DA neuron survival by regulating autophagy, and thus serves as a critical molecule in PD progression.

Keywords: Beclin 1; Parkinson’s disease; autophagy; dopaminergic neuron; serum response factor.