Senataxin, A Novel Helicase at the Interface of RNA Transcriptome Regulation and Neurobiology: From Normal Function to Pathological Roles in Motor Neuron Disease and Cerebellar Degeneration

Abstract

Senataxin (SETX) is a DNA-RNA helicase whose C-terminal region shows homology to the helicase domain of the yeast protein Sen1p. Genetic discoveries have established the importance of SETX for neural function, as recessive mutations in the SETX gene cause Ataxia with Oculomotor Apraxia type 2 (AOA2) (OMIM: 606002), which is the third most common form of recessive ataxia, after Friedreich's ataxia and Ataxia-Telangiectasia. In addition, rare, dominant SETX mutations cause a juvenile-onset form of Amyotrophic Lateral Sclerosis (ALS), known as ALS4. SETX performs a number of RNA regulatory functions, including maintaining RNA transcriptome homeostasis. Over the last decade, altered RNA regulation and aberrant RNA-binding protein function have emerged as a central theme in motor neuron disease pathogenesis, with evidence suggesting that sporadic ALS disease pathology may overlap with the molecular pathology uncovered in familial ALS. Like other RNA processing proteins linked to ALS, the basis for SETX gain-of-function motor neuron toxicity remains ill-defined. Studies of yeast Sen1p and mammalian SETX protein have revealed a range of important RNA regulatory functions, including resolution of R-loops to permit transcription termination, and RNA splicing. Growing evidence suggests that SETX may represent an important genetic modifier locus for sporadic ALS. In cycling cells, SETX is found at nuclear foci during the S/G cell-cycle transition phase, and may function at sites of collision between components of the replisome and transcription machinery. While we do not yet know which SETX activities are most critical to neurodegeneration, our evolving understanding of SETX function will undoubtedly be crucial for not only understanding the role of SETX in ALS and ataxia disease pathogenesis, but also for delineating the mechanistic biology of fundamentally important molecular processes in the cell.

San1 deficiency leads to cardiomyopathy due to excessive R-loop-associated DNA damage and cardiomyocyte hypoplasia

“…As a crucial transcriptional intermediate, R-loops likely contribute to the modulation of chromatin status, gene expression, and other crucial genomic processes [9,10] in cardiac development. Given the newly defined function of San1 in regulating DNA damage via interacting with SETX [14], a helicase that resolves R-loops [25], it is not a surprise that we found San1 deficiency leads to elevated R-loops in primary and AC-16 CMs. S9.6 immunofluorescent staining is a commonly used method to identify R-loops in cultured cells, but it also binds dsRNA with a weaker affinity that leads to false-positive staining [26].…”

“…Ubiquitylation of XRCC1 promotes its degradation through UPS [52]. Also, SUMOylation and ubiquitylation were thought to regulate the stability of SETX [25]. We found that hyperactivity of PARP1 in San1−/− cells negatively regulated the stability of SETX and XRCC1 through poly(ADP-ribose)-dependent ubiquitination (PARdU [51]).…”

Protective Mechanisms Against DNA Replication Stress in the Nervous System

“…Mutations in the SETX gene that encodes the protein senataxin are associated with two rare autosomal diseases of distinct inheritance: spinocerebellar ataxia, autosomal-recessive, with axonal neuropathy 2 (SCAN2, formerly known as AOA2, OMIM #606002), and amyotrophic lateral sclerosis 4 (ALS4, OMIM #602433), a juvenile form of ALS (Table 1). Despite sharing the same gene as a cause, SCAN2 is an autosomal-recessive disease characterized by loss-of-function mutations, while ALS4 is an autosomal-dominant trait associated with gain-of-function alterations [47,[165][166][167][168]. SCAN2 clinical manifestations include progressive cerebellar atrophy, ataxia, and sensorimotor peripheral neuropathy [169][170][171][172][173].…”

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 ].…”