The role of autophagy in clearance of aggregate‐prone proteins associated with disease

Intracellular aggregation of ubiquitinated proteins is a major cytopathological feature of most neurodegenerativedisorders, but also several forms of cancer are associated with aggregation of tumor suppressor proteins. Long considered a non‐selective process induced in response to cellular starvation, macroautophagy is now emerging as a highly selective quality control mechanism whose basal levels are important to prevent protein aggregate formation. The mechanisms responsible for selective autophagic degradation of ubiquitinated proteins, a process termed aggrephagy, are starting to become known and the ubiquitin‐ and LC3‐binding proteins p62 and NBR1 have been identified as specific cargo receptors. We have recently found that Alfy (autophagy‐linked FYVE protein), a large PI3P‐binding protein, is central to this selectivity. Alfy is recruited to intracellular inclusions and scaffolds a complex containing p62 and the autophagic effectors Atg5 and LC3. Depletion of Alfy inhibits clearance of huntingtin aggregates, but has no detectable effect on the non‐selctive starvation‐induced autophagy. Importantly, Alfy over‐expression diminishes inclusion number and leads to neuroprotection in a neuronal and Drosophila model of Huntington's disease, indicating that Alfy mediates selective macroautophagy of aggregating proteins.