TFEB: Pathogenic role and therapeutic target in Parkinson disease

Abstract

Parkinson disease (PD) is characterized by the progressive loss of nigral dopamine neurons and the presence of accumulations containing the disease-causing protein SNCA/α-synuclein. Here we review our recent findings describing how SNCA impairs the function of the master regulator of the autophagy-lysosomal pathway (ALP), the transcription factor EB (TFEB), and that genetic or pharmacological stimulation of its activity promotes protection of dopamine neurons. These findings suggest that strategies aimed at enhancing autophagy-mediated degradation of SNCA may hold great promise for disease intervention in PD.

Keywords: MIR128; Parkinson disease; TFEB; alpha-synuclein; dopamine; macroautophagy; neurodegeneration; temsirolimus.

Figure 1. SNCA-induced dysfunction of TFEB and therapeutic strategies. (A) Under physiological conditions, nuclear translocation of TFEB is controlled by MTOR. (B) In response to elevated levels of SNCA, an increase in nuclear TFEB is observed, resulting in the induction of autophagic and lysosomal genes. (C) If this compensatory mechanism fails, SNCA accumulates and sequesters TFEB in the cytoplasm. (D) Genetic or pharmacological stimulation of TFEB function promotes the clearance of toxic SNCA oligomers and afford protection of nigral dopamine neurons against SNCA toxicity.