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

Highlights

• SRF expression was reduced in rotenone-induced rats and cellular PD models.

• SRF served as a pro-survival factor to DA neurons against rotenone.

• SRF exerted protection via activation of Beclin 1-dependent autophagy activity.

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.

Introduction

Serum response factor (SRF) is a transcription factor involved in many biological processes, such as cellular migration, proliferation, and growth (Chai and Tarnawski, 2002, Schratt et al., 2004, Miano et al., 2007, Ro, 2016). It is highly expressed in the neurons of the central nervous system (Herdegen et al., 1997), where it regulates migration, neurite outgrowth, axon guidance, synaptic plasticity, and neuronal survival (Demir et al., 2011, Paul and Medina, 2012). In particular, SRF is highly abundant in the striatum, and is involved in modulating dopamine transmission (Parkitna et al., 2010). Several recent studies have implicated SRF dysregulation in the pathogenesis of neurodegenerative diseases. For instance, SRF was increased in the vascular smooth muscle cells of Alzheimer’s disease patients (Chow et al., 2007, Bell et al., 2009), but reduced in the hippocampus lysates of transgenic Huntington disease mice (Beck et al., 2012). The ablation of SRF enhanced the vulnerability of dopaminergic (DA) neurons in the substantia nigra (SN) to 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity, compared to the ventral tegmental area (Rieker et al., 2012), which indicated that SRF may contribute to the region-specific difference in the susceptibility of DA neurons in Parkinson’s disease (PD).

PD is the second most common neurodegenerative disorder, characterized by a progressive loss of DA neurons in the SN and the formation of α-synuclein-enriched inclusion bodies (Michel et al., 2016). A growing body of evidence shows that genetic factors and environmental toxins contribute to the development of PD. To date, the curative approaches for PD are limited because its pathogenesis remains elusive. Several pathogenic factors, including oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein misfolding, have been proposed to contribute to PD onset (Dauer and Przedborski, 2003). However, none of these hypotheses could fully address the neurochemical and pathological changes in PD. Therefore, further exploration of the cellular and molecular events leading to PD progression is required for identifying potential therapeutic target(s).

In this study, we demonstrated a decreased SRF level in the SN of rotenone-treated Lewis rats, as well as in cellular PD model. Moreover, our study showed that SRF protected PC12 cells against rotenone-induced toxicity and alleviated the accumulation of α-synuclein by regulating Beclin 1 expression and autophagy activity.