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Review
. 2024 Jul 15;6(4):fcae239.
doi: 10.1093/braincomms/fcae239. eCollection 2024.

Role of senataxin in R-loop-mediated neurodegeneration

Annapoorna Kannan  1 , Shyni Gangadharan Leela  2   3 , Dana Branzei  4   5 , Laxman Gangwani  2   3
Affiliations
Review

Role of senataxin in R-loop-mediated neurodegeneration

Annapoorna Kannan et al. Brain Commun. .

Abstract

Senataxin is an RNA:DNA helicase that plays an important role in the resolution of RNA:DNA hybrids (R-loops) formed during transcription. R-loops are involved in the regulation of biological processes such as immunoglobulin class switching, gene expression and DNA repair. Excessive accumulation of R-loops results in DNA damage and loss of genomic integrity. Senataxin is critical for maintaining optimal levels of R-loops to prevent DNA damage and acts as a genome guardian. Within the nucleus, senataxin interacts with various RNA processing factors and DNA damage response and repair proteins. Senataxin interactors include survival motor neuron and zinc finger protein 1, with whom it co-localizes in sub-nuclear bodies. Despite its ubiquitous expression, mutations in senataxin specifically affect neurons and result in distinct neurodegenerative diseases such as amyotrophic lateral sclerosis type 4 and ataxia with oculomotor apraxia type 2, which are attributed to the gain-of-function and the loss-of-function mutations in senataxin, respectively. In addition, low levels of senataxin (loss-of-function) in spinal muscular atrophy result in the accumulation of R-loops causing DNA damage and motor neuron degeneration. Senataxin may play multiple functions in diverse cellular processes; however, its emerging role in R-loop resolution and maintenance of genomic integrity is gaining attention in the field of neurodegenerative diseases. In this review, we highlight the role of senataxin in R-loop resolution and its potential as a therapeutic _target to treat neurodegenerative diseases.

Keywords: R-loops; SETX; ZPR1; amyotrophic lateral sclerosis 4; spinal muscular atrophy.

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Conflict of interest statement

The authors report no competing interests.

Figures

Graphical Abstract
Graphical Abstract
Figure 1
Figure 1
Mutations in SETX that result in gain of function, loss of function or SETX downregulation cause distinct human genetic neurodegenerative disorders. Graphical illustration of neurodegenerative disorders caused by SETX mutations with gain of function, loss of function and SETX downregulation. Gain-of-function mutations cause autosomal dominant ALS4 and autosomal dominant SMA (ADSMA); loss-of-function mutations cause autosomal recessive AOA2; and the downregulation of SETX levels associated with autosomal recessive SMA.
Figure 2
Figure 2
Molecular mechanism of SETX-dependent and R-loop-mediated neurodegeneration associated with SMA pathogenesis. (A) Chronic low levels of SMN cause downregulation of ZPR1 and SETX in SMA. The low endogenous levels of SETX–ZPR1 complexes result in poor assembly of RLRCs onto RNA:DNA hybrids during transcription, resulting in accumulation of R-loops. Increased accumulation of R-loops triggers SSBs and DSBs and causes activation of DDR pathways in SMA. DSB repair in neurons is predominantly mediated by NHEJ, which relies on the activation of DNA-PKcs. Chronic SMN deficiency also causes marked decrease in DNA-PKcs levels and its activation, resulting in inefficient NHEJ-mediated DNA repair in SMN-deficient neurons. Inefficient DSB repair in neurons results in accumulation of DNA damage leading to genomic instability and degeneration of neurons. (B) Cellular localization of SETX with core component of RNA resolution complexes (RLRC), including ZPR1, RNAPII and RNA:DNA hybrids. SETX is present in the cytoplasm and in the nucleus. SETX is an ATP-dependent RNA/DNA helicase that unwinds RNA:DNA hybrids formed during transcription. SETX interacts with ZPR1, RNAPII and RNA:DNA hybrids and co-localizes in sub-nuclear bodies, gems (SMN containing sub-nuclear bodies) and Cajal bodies. SETX is recruited onto R-loops by ZPR1. SETX, ZPR1 and RNAPII form endogenous complexes that assemble in vivo onto RNA:DNA hybrids formed during transcription and referred as to RLRC.
Figure 3
Figure 3
The molecular mechanism of R-loop resolution in normal and disease conditions. Left panel: Mechanism of R-loop resolution under normal conditions in mammalian cells. The key steps that contribute to R-loop resolution in mammalian cells are as follows: (i) ZPR1 binds to RNA/DNA hybrids, (ii) ZPR1 recruits SETX onto R-loops to initiate in vivo assembly of the core RLRC during transcription and (iii) SMN-dependent splicing machinery recruited to RLRC to initiate pre-mRNA processing. ZPR1 regulates the activity of SETX by controlling the speed of SETX-dependent R-loop resolution. ZPR1 regulates the R-loop resolution activity of SETX and thus may function as a ‘molecular brake’ to modulate the speed of SETX-dependent R-loop resolution and contributes to the survival and maintenance of neurons. Right panel: Mechanism of R-loop resolution under disease conditions in ALS4 patient-derived fibroblasts. Under ALS4 disease conditions, the following key steps contribute to R-loop resolution and disease pathogenesis: (i) interaction of ZPR1 with mutant SETX (L389S) shown as SETX* is disrupted. ZPR1 fails to recruit mutant SETX homodimer (SETX*–SETX*) but recruits heterodimer (SETX–SETX*) to R-loops. However, partial disruption of molecular interaction between ZPR1 and SETX* in the ZPR1–SETX–SETX* complex impairs ZPR1's ability to regulate R-loop resolution activity of mutant SETX* resulting in fewer R-loops in ALS4. In summary, mutations in SETX disrupt its interaction with ZPR1 causing partial impairment of the molecular brake, resulting in increased speed (activity) of SETX-dependent R-loop resolution (gain of function). The low levels of R-loops alter gene expression resulting in dysregulation of the TGF-β signalling pathway critical for neuron survival.
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