Neurobiological Basis of Neuronal Survival

National Institute On Drug Abuse

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Abstract

Macroautophagy/autophagy is an essential process for cellular survival and is implicated in many diseases. A critical step in autophagy is the transport of the transcription factor TFEB from the cytosol into the nucleus, through the nuclear pore (NP) by KPNB1/importin1. In the C9orf72 subtype of amyotrophic lateral sclerosis-frontotemporal lobar degeneration (ALS-FTD), the hexanucleotide (G4C2)RNA expansion (HRE) disrupts the nucleocytoplasmic transport of TFEB, compromising autophagy. We previously showed that a molecular chaperone, the SIGMAR1/Sigma-1 receptor (sigma non-opioid intracellular receptor 1), facilitates TFEB transport into the nucleus by chaperoning the NP protein (i.e., nucleoporin) POM121 which recruits KPNB1. In NSC34 cells, HRE reduces TFEB transport by interfering with the association between SIGMAR1 and POM121, resulting in reduced nuclear levels of TFEB, KPNB1, and the autophagy marker LC3-II. In this fiscal year we found that (i) a treatment with the highly selective and potent SIGMAR1 agonist fluvoxamine, a ligand with higher affinity at sigma-1 receptor than at 5HT receptor, rescues all of these ALS-FTD-like deficits. Our results implicate nucleoporin POM121 not merely as a structural nucleoporin, but also as a chaperone-operated signaling molecule enabling TFEB-mediated autophagy. Our data also suggest the use of SIGMAR1 agonists, such as fluvoxamine, for therapeutic development of diseases in which autophagy is impaired. Thus fluvoxamine, a clinical used drug, can be repurposed for treatment against neurodegenerative diseases that are characterized by a deficiency in autophagy; (ii) the sigma-1R–Pom121 axis is also very important in preserving nuclear transport and integrity in the toxic peptide "Poly-PR"-induced C9orf72 ALS. Both studies are published in peer-reviewed journals this year.