DECODING AUTOPHAGOSOMES: A CLUE TO PARKINSON'S, HUNTINGTON'S, DEMENTIA

By René A. Azeez, Honours BSc. Developmental Biology, University of Toronto. July 27, 2011.

         A paper centered on autophagy, the catabolic process by which a cell degrades its intercytoplasmic components transported in double-membraned autophagosomes by the action of its lysosomal machinery, may have implications in understanding the development of many neurodegenerative diseases, including Huntington’s disease, Parkinson’s disease, and dementia. Research from the Rubinsztein lab at the Cambridge Institute for Medical Research had previously demonstrated autophagy as an important regulator of the levels of proteins and pathogens prone to aggregation which in turn play a role in the development of these and potentially other diseases. In fact, apart from regulation of numerous physiological and pathological processes, and innate and acquired immunity, it is hypothesized that autophagosome function may play a role in cancer, infectious diseases, and ageing.

         Preautophagosomal structures stemming from the plasma membrane and other cellular sites form phagophores which in turn elongate and undergo fusion to become autophagosomes. However, the mechanism which governs the maturation of preautophagosomes to fully formed autophagosomes is largely unknown. A recent study from the same group at the Cambridge Institute for Medical Research entitled “Autophagosome Precursor Maturation Requires Homotypic Fusion” attempted to shed some light on the mechanism. More than 30 autophagy related proteins (Atg) have been previously shown to play some role in regulating autophagy. In this study, researchers were able to reveal that Atg16L1 precursors underwent homotypic fusion in order to form mature autophagosomes. This increases the size of the vesicles which appears to enhance acquisition of LC3, a key autophagosome protein, and maturation into autophagosomes. Furthermore, they were able to determine through a combination of colocalization analysis, knockdown experiments, live cell imaging, in vitro fusion assay, HCS and Image J methods etc., that the homotypic fusion of Atg16L1 precursors is dependant on the SNARE protein VAMP7 together with partner SNARE proteins including syntaxin 7, syntaxin 8, and Vti1b.

         By understanding new steps in the formation of autophagosomes, researchers have given insight and possible new therapeutic direction to the management of the many diseases and conditions for which autophagy plays a role.

REFERENCE:

Moreau K., Ravikumar B., Renna M., Puri C, and Rubinsztein D. C. Autophagosome precursor maturation requires homotypic fusion. 2011. Cell (146): 303-317.