Autophagy regulation by acetylation-implications for neurodegenerative diseases

Neurodegeneration: Altered protein tagging impairs brain's clean-up mechanisms Modulation of a chemical tagging process known as acetylation could help brain cells remove toxic proteins associated with Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. David Rubinsztein and colleagues from the University of Cambridge, UK, review how enzymes that add or remove acetyl groups to or from proteins help to regulate autophagy, the process whereby damaged cellular components are removed. In neurons, imbalanced acetylation can result in the toxic build-up of proteins such as tau (Alzheimer's disease), alpha-synuclein (Parkinson's disease), huntingtin (Huntington's disease) and superoxide dismutase 1 (ALS). The ensuing protein aggregation can then trigger progressive neuron loss and impaired function, especially as the brain ages. The authors propose that therapeutic targeting of acetylation to restore healthy autophagic activity could therefore have neuroprotective effects in many of these diseases. Posttranslational modifications of proteins, such as acetylation, are essential for the regulation of diverse physiological processes, including metabolism, development and aging. Autophagy is an evolutionarily conserved catabolic process that involves the highly regulated sequestration of intracytoplasmic contents in double-membrane vesicles called autophagosomes, which are subsequently degraded after fusing with lysosomes. The roles and mechanisms of acetylation in autophagy control have emerged only in the last few years. In this review, we describe key molecular mechanisms by which previously identified acetyltransferases and deacetylases regulate autophagy. We highlight how p300 acetyltransferase controls mTORC1 activity to regulate autophagy under starvation and refeeding conditions in many cell types. Finally, we discuss how altered acetylation may impact various neurodegenerative diseases in which many of the causative proteins are autophagy substrates. These studies highlight some of the complexities that may need to be considered by anyone aiming to perturb acetylation under these conditions.

Automated summary

Acetylation plays a crucial role in neurodegenerative diseases by affecting the clearance and aggregation of proteins, leading to neuron loss and impaired function. Therapeutic targeting of acetylation to restore healthy autophagic activity may have neuroprotective effects in various neurodegenerative diseases. These findings highlight the importance of understanding the role of acetylation in regulating autophagy for the development of potential treatments for neurodegenerative disorders.