Implications of Selective Autophagy Dysfunction for ALS Pathology

Abstract

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder that progressively affects motor neurons in the brain and spinal cord. Due to the biological complexity of the disease, its etiology remains unknown. Several cellular mechanisms involved in the neurodegenerative process in ALS have been found, including the loss of RNA and protein homeostasis, as well as mitochondrial dysfunction. Insoluble protein aggregates, damaged mitochondria, and stress granules, which contain RNA and protein components, are recognized and degraded by the autophagy machinery in a process known as selective autophagy. Autophagy is a highly dynamic process whose dysregulation has now been associated with neurodegenerative diseases, including ALS, by numerous studies. In ALS, the autophagy process has been found deregulated in both familial and sporadic cases of the disease. Likewise, mutations in genes coding for proteins involved in the autophagy machinery have been reported in ALS patients, including selective autophagy receptors. In this review, we focus on the role of selective autophagy in ALS pathology.

Keywords: NBR1; TBK1; amyotrophic lateral sclerosis; autophagy; optineurin; p62; ubiquilin2.

Figure 1

Selective autophagy under physiological and ALS pathological conditions. Protein aggregates, stress granules, and dysfunctional mitochondria are substrates for selective autophagy degradation. Under physiological conditions (upper panel), substrates are bound by selective autophagy receptors, such as p62, OPTN and NBR1 (represented in dark blue) via ubiquitin-binding domains (ubiquitin, in green). Selective autophagy receptors associate with LC3 proteins in the autophagosome (represented in yellow), or other members from the autophagy machinery. Posttranslational modifications in the receptors can enhance the binding with ubiquitinated substrates or the LC3 protein. TBK1 is one of the main kinases acting in this process. The cargo-receptor-LC3 complexes are then sequestered by de novo double-membrane vesicles called the autophagosome, which fuses with the lysosome for the final degradation. Under ALS conditions (lower panel), the failure in selective autophagy can occur through mutations in the genes encoding the receptors themselves or in the TBK1 gene, reducing the activity of the pathway, promoting the accumulation of toxic substrates for motor neurons (Image created with BioRender.com).