Autophagy as a common pathway in amyotrophic lateral sclerosis

Abstract

Age-dependent neurodegenerative diseases are associated with a decline in protein quality control systems including autophagy. Amyotrophic lateral sclerosis (ALS) is a motor neuron degenerative disease of complex etiology with increasing connections to other neurodegenerative conditions such as frontotemporal dementia. Among the diverse genetic causes for ALS, a striking feature is the common connection to autophagy and its associated pathways. There is a recurring theme of protein misfolding as in other neurodegenerative diseases, but importantly there is a distinct common thread among ALS genes that connects them to the cascade of autophagy. However, the roles of autophagy in ALS remain enigmatic and it is still unclear whether activation or inhibition of autophagy would be a reliable avenue to ameliorate the disease. The main evidence that links autophagy to different genetic forms of ALS is discussed.

Keywords: ALS; Alsin; Autophagy; C9orf72; CHMP2B; Dynactin; FIG4; FTD; FUS; Optineurin; Profilin; SOD1; TBK1; TDP-43; UBQLN2; VAPB; VCP; p62.

Figure 1. Schematic representation of ALS-related genes and their modulatory effects on autophagy

The spectrum of ALS-associated genes and their various modulatory effects upon autophagy entailing the stages of autophagy initiation, autophagosome maturation, and autophagosome-lysosome/endosome fusion are depicted herein. Proteins prone to aggregation are highlighted in yellow, those involved in autophagic initiation and autophagosome formation in red, those involved in endosome trafficking and the autophagosome-lysosome fusion in green, and those with less defined roles in autophagy are signified in white.