Beclin-1 and Autophagy: Potential for New Therapeutics in Neurodegeneration

Abstract

ISSN 1758-2024 10.2217/NMT11.56 © 2011 Future Medicine Ltd Neurodegen. Dis. Manage. (2011) 1(5), 349–351 Autophagy is a cellular quality control system responsible for the degradation of cytosolic components in lysosomes [1]. It involves confinement in double membrane vesicles, termed autophagosomes, of proteins and damaged organelles, which upon fusion with the lysosome are degraded by acid hydrolases. Autophagy has a vital function in promoting cell survival, particularly protein clearance, defence against pathogens and adaptation to nutrient and oxygen-deficient conditions. Nevertheless, until recently, the role of autophagy in neurons was uncertain and compelling evidence of the crucial role of autophagy in postmitotic cells such as neurons was only obtained in recent years, when its major importance became apparent, not only for diseases related to protein aggregation, but also as a housekeeping mechanism of the CNS (reviewed in [1]). For this contributed decisively the finding that mice lacking either the autophagic gene 7 or 5 suffer neurodegeneration despite a normal ubiquitinproteasome system function, an observation that was a major breakthrough for the n eurosciences and autophagy field [2,3]. Among the vital autophagic genes, the mammalian homologue of the yeast autophagic gene 6, Beclin‐1, has been implicated as a fundamental regulator of autophagy, not only for the nucleation of the autophagosomes, but also for the maturation step of the pathway [4,5]. Beclin-1 appears to play a general role in cell survival. In mice, homozygous deletions of this gene (Bec), led to death at an early embryonic stage [6] while heterozygous deletions (Bec) led to an increased frequency of spontaneous tumors [6], as well as alterations in neuronal autophagy and neuronal function [7]. In 2004, Shibata and colleagues were the first to explore Beclin‐1 mRNA and protein levels in aged and Huntington’s disease-affected brains [8]. The authors found an age-dependent decrease of Beclin-1 levels in human brains and sequestration of Beclin-1 into the mutant Huntingtinaggregates [8]. In 2008, the first report on the protective effects of overexpressing Beclin‐1 in a neurodegenerative disease was published [7]. Endogenous protein levels of Beclin-1 were found decreased in