Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating human neurodegenerative disease. The causes of ALS are poorly understood, although the protein TDP-43 has been suggested to play a critical role in disease pathogenesis. Here we show that Ataxin-2, a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2 (SCA2), is a potent modifier of TDP-43 toxicity in animal and cellular models. The proteins associate in a complex that depends on RNA. Ataxin-2 is abnormally localized in spinal cord neurons of ALS patients. Likewise, TDP-43 shows mislocalization in SCA2. To assess a role in ALS, we analyzed the Ataxin-2 gene (ATXN2) in 915 ALS patients. We found intermediate-length polyQ expansions (27–33 Qs) in ATXN2 significantly associated with ALS. These data establish ATXN2 as a relatively common ALS disease susceptibility gene. Further, these findings indicate that the TDP-43/Ataxin-2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.

The phenotypic variability of amyotrophic lateral sclerosis

“…70,88 Interestingly, SCA type 2, which is caused by a CAG expansion in ATXN2, has genotypic and phenotypic overlap with ALS. Intermediate-length expansions in ATXN2 are a risk factor for ALS-but, strangely enough-not for ALS-FTD or FTD 89,90 -and ATXN2 mutations can present as ALS. 91 The biological basis for the link between SCA and ALS is unknown.…”

The Multiple Faces of Spinocerebellar Ataxia type 2

“…Based on interaction between ataxin‐2 and TDP‐43, a protein involved in ALS pathogenesis, Elden et al investigated ataxin‐2 as a risk factor for ALS in North American population 85. More than twice as many patients with ALS compared to a control population had ataxin‐2 polyglutamine repeat length in the high spectrum, within normal range (≥24 glutamines).…”

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

“…The RNA-binding domains of TDP43 and FUS are essential for toxicity in ALS model systems, testifying to the importance of RNA dysregulation in ALS pathogenesis [34,[39][40][41]. Immunoprecipitation studies in murine brain [14], dissociated primary cortical neurons [37], and human brain [13] and cell lines [13,38] showed that TDP43 recognizes nearly one-thrid of all transcribed genes by binding to redundant GU-rich sequences [42].…”

“…Deletion of the RNA-binding domains in TDP43 and FUS both prevents their inclusion in stress granules and reduces their toxicity [34,[39][40][41]. Moreover, components of stress granules have been detected in TDP43-rich cytoplasmic deposits in spinal neurons of patients with ALS [56,99,101], but are less common in cortical neurons [102].…”

“…Supporting the connection between abnormal RNA processing and motor neuron disease, nonsense or missense mutations in FUS, EWSR1, and TAF15 are associated with fALS [30,31]. Moreover, trinucleotide (CAG) expansion mutations in ATXN2, encoding the RNA-binding protein ataxin-2, cause spinocerebellar ataxia or ALS, depending on the number of CAG repeats [32][33][34][35], and, in some populations, hexanucleotide (G 4 C 2 ) expansion mutations in the noncoding region of the C9orf72 locus account for up to 40 % of fALS [17,18]. Individuals carrying C9orf72 expansion mutations also exhibit RNA-rich nuclear foci, indicative of fundamental abnormalities in RNA metabolism.…”