Keyword
Introduction
Accumulation and aggregation of mutant proteins is a hallmark of several neurodegenerative disorders such as Parkinson’s, Alzheimer’s, and Huntington’s disease (HD) (Ross and Poirier, 2004). One of the major therapeutic challenges in the field of neurodegeneration has been to improve the degradation of accumulated mutant proteins. While the ubiquitin-proteosome system (UPS) represents an important defense against abnormal protein accumulation, aggregation-prone proteins appear to be poor substrates for proteosomal degradation and better targets for autophagic-lysosomal degradation (Levine and Kroemer, 2008). In terms of the mode of cargo delivery to the lysosome, three forms of autophagic degradation have been described so far—microautophagy, chaperone-mediated autophagy, and macroautophagy (Klionsky, 2007). This latter form, whereby cytosolic constituents and organelles are engulfed by multilamellar vesicles which then fuse to the lysosome, has been implicated in a wide array of neurological disorders including HD (Cuervo, 2004; Nixon, 2005; Levine and Kroemer, 2008).
Huntington’s disease is a devastating neurodegenerative disorder characterized by progressive and severe motor and cognitive impairment; death ensues about 15 years after the onset of symptoms (Vonsattel and DiFiglia, 1998). The mutation is inherited as autosomal dominant and causes expansion of a stretch of glutamines near the N terminus of huntingtin, a protein of uncertain function whose mutant form accumulates as nuclear and cytoplasmic inclusions in HD brain (DiFiglia et al., 1997). In a conditional mouse model of HD, it was found that elimination of mutant Huntingtin (Htt) expression not only halted symptomatic progression but also led to regression of the disease-like symptoms (Yamamoto et al., 2000). Initial experiments in human HD brain found aberrant accumulation of huntingtin in late endosomal structures, suggesting dependence on autophagy (Sapp et al., 1997). Recent findings showed that activation of autophagy by systemic administration of rapamycin may be sufficient to partially ameliorate symptoms in an HD mouse model (Ravikumar et al., 2004). While these and other studies demonstrate neuroprotection by the inhibition of the ubiquitous protein kinase mTOR and nonspecific activation of autophagy, it remains unclear whether autophagy can be selectively activated in order to remove disease proteins of interest.
In this study, we demonstrate a link between acetylation of a nonhistone protein and targeted degradation by autophagy. Modification of mutant huntingtin by acetylation promotes its targeting into autophagosomes and facilitates specific degradation of the mutant protein by the autophagic-lysosomal pathway. Furthermore, we show that acetylation and clearance of mutant huntingtin leads to neuroprotection in primary neurons and a transgenic C. elegans model of HD, highlighting the importance of selective targeting of disease proteins to autophagosomes for degradation.
