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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a complex, multifactorial disease with genetic and environmental risk factors, with many genes involved in several pathophysiological pathways, which represents a challenge in research
The accumulation of protein aggregates, stress granules (SGs), and RNA inclusions are features of motor neurons neurodegenerating in ALS
Several of the genes affected in ALS encode proteins related to the autophagy machinery itself, highlighting the relevance of the pathway to motor neuronal homeostasis, but limiting interventions based on autophagy as a therapeutic approach
Summary
Amyotrophic lateral sclerosis (ALS) is one of the most common adult diseases characterized by the loss of upper and lower motor neurons in the brain, brainstem, and spinal cord, causing progressive paralysis of the voluntary muscles [1]. Mutations in SOD1 trigger its misfolding and aggregation, a phenomenon observed for its wild-type protein in sALS cases [7,8]. Mutations in the TARDBP gene, coding for Tar DNA binding protein 43 (TDP43), one of the most common components of protein aggregates in ALS cases, were identified. Mutations in six genes can explain about 60–70% of fALS and about 10% of sALS cases: SOD1, TARDBP, FUS (fused in sarcoma), VCP (valosin-containing protein), OPTN (optineurin), and C9orf72 [4,9]. As an intracellular hallmark of ALS, motor neurons present an accumulation of protein aggregates and dysfunctional organelles, such as mitochondria. Several of the genes in which mutations are associated with ALS encode proteins that take part in the protein quality control machinery, are part of the disease etiology themselves
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