The altered autophagy mediated by TFEB in animal and cell models of amyotrophic lateral sclerosis.

Autophagy is an intracellular degradation process that clears away aggregated proteins or aged and damaged organelles. Abnormalities in autophagy result in defects in clearance of these misfolded and aggregate proteins, which have been associated with neurodegenerative disorders. A key neuropathological hallmark of amyotrophic lateral sclerosis (ALS) that contributes to the progressive loss of motor neurons is abnormal protein aggregation of mutant Cu/Zn superoxide dismutase1 (SOD1). TFEB is a recently described gene that regulates autophagy. Several studies have reported that autophagy is altered in ALS, but little is known about the role and mechanisms of TFEB-mediated autophagy during the progression of ALS. In this study, altered expression of TFEB and Beclin-1 were detected in the spinal cords of ALS transgenic mice at different stages and in an NSC-34 cell model with the SOD1-G93A mutation using RT-PCR, western blot, and immunohistochemistry. The majority of cells positive for TFEB and Beclin-1 are β-tubulin III-labeled neurons, especially in the anterior horn of the gray matter. Overexpression of TFEB in NSC-34 cells with the SOD1-G93A mutation increased the mRNA and protein levels of Beclin-1, accompanied by increased levels of LC3-II protein. MTS assay revealed that TFEB overexpression increased proliferation and survival of NSC-34 cells with the SOD1-G93A mutation. Our findings suggest that TFEB promotes autophagy by enhancing the expression of Beclin-1. The altered autophagy mediated by TFEB is a key element in the pathogenesis of ALS, making TFEB a very promising target for the development of novel drugs and new gene therapeutics for ALS.