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Review
. 2021 Aug 1;34(4):578-588.
doi: 10.1097/WCO.0000000000000959.

Ataxin-2 gene: a powerful modulator of neurological disorders

Jose Miguel Laffita-Mesa  1 , Martin Paucar, Per Svenningsson
Affiliations
Review

Ataxin-2 gene: a powerful modulator of neurological disorders

Jose Miguel Laffita-Mesa et al. Curr Opin Neurol. .

Abstract

Purpose of review: To provide an update on the role of Ataxin-2 gene (ATXN2) in health and neurological diseases.

Recent findings: There is a growing complexity emerging on the role of ATXN2 and its variants in association with SCA2 and several other neurological diseases. Polymorphisms and intermediate alleles in ATXN2 establish this gene as a powerful modulator of neurological diseases including lethal neurodegenerative conditions such as motor neuron disease, spinocerebellar ataxia 3 (SCA3), and peripheral nerve disease such as familial amyloidosis polyneuropathy. This role is in fact far wider than the previously described for polymorphism in the prion protein (PRNP) gene. Positive data from antisense oligo therapy in a murine model of SCA2 suggest that similar approaches may be feasible in humans SCA2 patients.

Summary: ATXN2 is one of the few genes where a single gene causes several diseases and/or modifies several and disparate neurological disorders. Hence, understanding mutagenesis, genetic variants, and biological functions will help managing SCA2, and several human diseases connected with dysfunctional pathways in the brain, innate immunity, autophagy, cellular, lipid, and RNA metabolism.

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Conflict of interest statement

There are no conflicts of interest.

Financial Disclosure: None

Figures

Box 1
Box 1
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FIGURE 1
FIGURE 1
Mutagenesis, founder effect and ATXN2 isoforms. (A) Mutagenesis in SCA2 is thought to occurs under predisposed haplotypes, where 5’ CAA interruption loss occurs with more propensity [5,6]. (B) Low range CAG repeats interrupted by CAA (33–34repeats) shared the same STR-SNP haplotype, loci: D12S1333, D12S1672, rs695871 and rs695872, with uninterrupted full expansions [7]. (C) Prediction of the age for the Cuban SCA2 founder effect with DMLE [9] using six STR markers (D12S1328-D12S1332-D12S1672-D12S1333- D12S1329-88-5) in the vicinity of SCA2 mutation in 13 affected families. The curve represents the probability density of the mutation age for growth rate 0.45 within the period 1774–2007. The dashed lines correspond to the 95% credible set of values. The origin was predicted to have occurred 15 generations ago. According to this, the founder effect occurred likely 375 years ago, at year ∼1615 which is 70 years after the Holguin Villa foundation. (D) Isoform Expression of ATXN2 in different tissues (https://gtexportal.org/home/gene/ENSG00000204842.14#gene-transcript-browser-block). ATXN2, Ataxin-2 gene; CAG, cytosine adenine guanine; STR-SNP, short tandem repeat-single nucleotide polymorhphism.
FIGURE 2
FIGURE 2
Novel ATXN2 variants and aberrant Splice variant profiles. (A) Deletion (17 bases) at 12-111599394 in ATXN2 (p.Ala35GlyfsTer39). (B) Local alignment for the first exon of wild-type ATXN2 and the predicted polypeptide resulting from the 17 bp deletion. (C) Typical fragment analysis traces for the ATXN2-AS gene expression profiling in healthy controls (top) and cases with ATXN2 duplication mutation of 9 bp duplication (bottom). Two ATXN2-AS splice variants were analyzed v1 (∼800 bp) and v2 (∼450 bp), arrows indicate the predicted length. In addition to the expected bands, other bands can be seen at 360, 480, 600–760 bp. Strand Specific-RT-PCR was performed in cDNA using primers and conditions previously published [22] with small modifications. Two rounds of PCR were done, and samples were ten-fold replicated. To obtain a pool of amplicons, 5ul of cDNA was amplified with R2/LK-F6 or LK-F7 primers and a second PCR amplification of 1/100 of the first PCR was done with LK/R3–6FAM primers. Five microliters of reaction amplicons were cleaned with 2ul ExoSAP-IT Express PCR and were mixed with GeneScan 1200 LIZ dye Size Standard (Applied Biosystems) and were ran during 4hrs with 50 cm capillary by Capillary Electrophoresis in a 3730 genetic Analyzer. Peak Scanner software was used to obtain splice variants sizes and height peaks. The data table was exported directly to be analyzed using height peaks≥150 and size ≥300. (D) Histogram with ATXN2-AS splice variant profile. Peaks showing differences of 40 bp sizes were binned together for data presentation purposes.
FIGURE 3
FIGURE 3
Variable phenotype may involve the CAA interruptions within the ATXN2 CAG repeats. This may entail different interactors at different pathological hits, but the most likely is the level involving RNA/RNA-binding proteins. CAG, cytosine adenine guanine.
FIGURE 4
FIGURE 4
ATXN2 function and RNA metabolism in health and disease. For efficient protein synthesis, ATXN2 C-terminal PAM2 motif mediates interaction with the poly(A)-binding protein PABPC1 tethered to poly-(A) 3′tail mRNAs [40]. This complex interacts with eIF4GI at the 5′ tail, creating the required circularization mRNA linking 5′-3′ ends. Yokoshi et al. found that ATXN2 binds, stabilizes, and regulates the translation of more than 4,000 mRNA molecules [41]. For this, ataxin-2 predominantly binds to AU rich cis-regulatory elements at the 3′ tail of target mRNAs. The breadth of cellular processes targeted by this ATXN2 functions includes RNA splicing, mRNA polyadenylation, 3′tail processing and cellular metabolism. The pathological polyQ expansion perturbs this ataxin-2 physiological role, as Q31 (ALS) and Q39 (SCA2) downregulates the abovementioned processes in a dependent polyQ length manner [41]. It was not clear how ATXN2 stabilizes its target transcriptome, but Inagaki et al. showed polyadenylation enzymatic activity for ATXN2 [55]. The mechanism implies that ATXN2 binds to both cis-regulatory elements in the target mRNA and to PABP and others RNP trough the PAM2 motif. This complex may activate and stabilize their target transcriptome, for instance TDP43 and Cyclin-D1, through catalytic polyadenylation. In turn, TDP43 protein accelerates deadenylation of target mRNAs, which is a critical step in the RNA degradation. Therefore, regulating the length of the of the poly(A) tail plays a key role in the control of the mRNA stability [42▪]. This provides evidence for a common cellular process where both proteins cooperate with antagonistic functions regulating common substrates. Likewise, could suggest that an immediate pathological consequence of the abnormal interaction driven by polyQ in ATXN2, would be the loss of TDP43 function when work on stabilizing and activating their common transcriptomes. This may also affect the regulation of circadian genes as Drosophila ATX2 complex may switch distinct modes of posttranscriptional regulation through its associating factors to control circadian clocks and ATX2-related physiology [43]. It is not clear whether ATXN2 undergone any other posttranslational modification like the pathological TDP43 phosphorylation. ALS, amyotrophic lateral sclerosis.
FIGURE 5
FIGURE 5
Prodromal SCA2 and biomarkers. (A) Identification of preclinical biomarkers in biological fluids and fibroblasts, paralleled with MRI and standardized clinical evaluation in asymptomatic individuals at risk [57]. Importantly, individuals are not aware of their genetic statuses. This approach, will be of great help in local or global SCA projects aimed at uncovering wet biomarkers like free circulating DNA, expanded ataxin-2 in CSF, somatic mosaicism, neurofilaments, DNA/RNA-derivatives improving the read outs for future trials. BC) SCA2 is featured by two major stages, early on it is featured by the nonmotor phase and later by a predominant and invaliding motor stage. Genetic factors or therapies acting in early stages have the potential to slowdown the neurodegeneration and postpone the onset of ataxic symptoms. Arrows in the bottom suggest potential time points for therapies targeting modifiers or disease causative factors. SCA2, spinocerebellar ataxia 2.
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