Disease mechanism illuminated through study of cell and mouse models in Angelman syndrome

In a groundbreaking study published in the journal Experimental Neurology, researchers have discovered an increase in autophagy in cell and mouse models of Angelman syndrome (AS). This neurological disorder, caused by a missing or dysfunctional copy of the UBE3A gene, has long been associated with impairments in various cellular processes, but the role of autophagy in AS hasn't been established until now.

The study, led by Dr. Inacio, PhD FDA, reveals that the movement of a molecule called TFEB into the cell's nucleus could possibly contribute to the enhancement in autophagy seen. This process, where cellular waste is recycled in compartments called lysosomes, is another way of getting rid of waste in cells.

The researchers found an elevation in an active form of AMPK in AS mice relative to healthy mice. AMPK, a key player in energy balance and metabolism, is involved in the initiation of autophagy in part through its activation of the ULK1 protein. Levels of active ULK1 were similarly elevated in AS mice.

Interestingly, the protein p53, which regulates autophagy, was found to have a non-significant increase in its levels in the nucleus of cells from AS mice, while its levels were significantly decreased in the cytoplasm. This suggests a complex interplay of p53 in the regulation of autophagy in AS.

Markers of increased autophagy were observed not only in the cell model but also in the cerebellum of AS mice compared with healthy mice. The researchers indicated that UBE3A deficiency increases autophagy activity in AS samples.

Recent studies have revealed dynamic interconnections and metabolic compensation between the ubiquitin-proteasome system (UPS) and autophagy. UBE3A is responsible for producing the UBE3A protein, a key player in the UPS. The scientists believe that the autophagy increase is "most likely caused by increased AMPK activation followed by ULK1 activation," with possible contributions from other pathways.

Whether enhanced autophagy is a compensatory mechanism to sustain metabolic homeostasis or a pathogenic process for AS remains to be determined. However, the study's findings may have broad implications for diseases where autophagy and related mechanisms play a role.

Impairments in autophagy have been linked to various diseases, but its role in AS hasn't been established until now. This study provides valuable insights into the complex cellular processes involved in AS and opens up new avenues for potential therapeutic strategies.

Disease mechanism illuminated through study of cell and mouse models in Angelman syndrome