SETX (senataxin), the helicase mutated in AOA2 and ALS4, functions in autophagy regulation

Abstract

SETX (senataxin) is an RNA/DNA helicase that has been implicated in transcriptional regulation and the DNA damage response through resolution of R-loop structures. Mutations in SETX result in either of two distinct neurodegenerative disorders. SETX dominant mutations result in a juvenile form of amyotrophic lateral sclerosis (ALS) called ALS4, whereas recessive mutations are responsible for ataxia called ataxia with oculomotor apraxia type 2 (AOA2). How mutations in the same protein can lead to different phenotypes is still unclear. To elucidate AOA2 disease mechanisms, we first examined gene expression changes following SETX depletion. We observed the effects on both transcription and RNA processing, but surprisingly observed decreased R-loop accumulation in SETX-depleted cells. Importantly, we discovered a strong connection between SETX and the macroautophagy/autophagy pathway, reflecting a direct effect on transcription of autophagy genes. We show that SETX depletion inhibits the progression of autophagy, leading to an accumulation of ubiquitinated proteins, decreased ability to clear protein aggregates, as well as mitochondrial defects. Analysis of AOA2 patient fibroblasts also revealed a perturbation of the autophagy pathway. Our work has thus identified a novel function for SETX in the regulation of autophagy, whose modulation may have a therapeutic impact for AOA2.

Juvenile Amyotrophic Lateral Sclerosis: A Review

“…Senataxin mutations are also associated with ataxia with oculomotor apraxia type 2 (AOA2) [ 27 , 28 , 29 ]. This autosomal recessive disorder is characterized by cerebellar ataxia, oculomotor apraxia, axonal sensorimotor neuropathy, and elevated serum α-fetoprotein.…”

“…Spatacsin may function in the maintenance of cytoskeleton stability and regulation of synaptic vesicle transport. The age of onset for SPG11-JALS ranges from 7 to 23 years, with onset most commonly in the second decade and a disease duration of 34.3 years (range of [27][28][29][30][31][32][33][34][35][36][37][38][39][40]. The clinical presentation begins with distal LMN upper or lower extremity weakness combined with UMN signs.…”

A Novel SETX Mutation in a Taiwanese Patient with Autosomal Recessive Cerebellar Ataxia Detected by Targeted Next-Generation Sequencing, and a Literature Review

“…Senataxin contains a DNA/RNA helicase domain at its C-terminus, which shows homology to the helicase domain of the yeast protein Sen1p and an N-terminal domain that is important for protein–protein interaction [ 1 ]. Senataxin has been shown to play important roles in transcription regulation, protecting the integrity of the genome against oxidative and other forms of DNA damage [ 2 ], neuritogenesis [ 3 ], spermatogenesis [ 4 ], and autophagy [ 5 ]. Mutations in SETX are also associated with the phenotype of juvenile-onset Amyotrophic Lateral Sclerosis (ALS) [ 5 , 6 ].…”

“…Senataxin has been shown to play important roles in transcription regulation, protecting the integrity of the genome against oxidative and other forms of DNA damage [ 2 ], neuritogenesis [ 3 ], spermatogenesis [ 4 ], and autophagy [ 5 ]. Mutations in SETX are also associated with the phenotype of juvenile-onset Amyotrophic Lateral Sclerosis (ALS) [ 5 , 6 ]. AOA2/SCAN2 belongs to the group of neurological conditions known as Autosomal Recessive Cerebellar Ataxias (ARCAs), which currently comprises over 40 disorders.…”

De novo pathogenic variant in SETX causes a rapidly progressive neurodegenerative disorder of early childhood-onset with severe axonal polyneuropathy

“…SETX encodes for senataxin, an RNA/DNA helicase with multiple critical roles including transcriptional regulation, RNA processing, maintenance of genome integrity and the DNA damage response, neurogenesis, regulation of autophagy, and antiviral response [ 11 , 20 , 35 , 39 ]. Two well-described neurodegenerative phenotypes have been associated with pathogenic variants in SETX : autosomal recessive ataxia with oculomotor apraxia type 2 (AOA2; also known as Spinocerebellar Ataxia with Axonal Neuropathy Type 2, SCAN2), and an autosomal dominant juvenile-onset form of motor neuron disease, Amyotrophic Lateral Sclerosis Type 4 (ALS4) [ 5 , 15 ].…”