Unraveling the Role of Ataxin-2 in Metabolism

Carmo‐Silva, Sara; Matos, Carlos A.; Almeida, Luís Pereira de; Cavadas, Cláudia

doi:10.1016/j.tem.2016.12.006

Cited by 32 publications

(29 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this section, we highlight the functions of Ataxin-2 related to TORC1 signaling and circadian rhythms. For a review focusing on the function of Ataxin-2 in cell metabolism, we refer the reader elsewhere [52]. …”

Section: Wide-ranging Molecular Functions Of Ataxin-2mentioning

confidence: 99%

Ataxin-2: From RNA Control to Human Health and Disease

Ostrowski

Hall

Mekhail

2017

Genes

View full text Add to dashboard Cite

RNA-binding proteins play fundamental roles in the regulation of molecular processes critical to cellular and organismal homeostasis. Recent studies have identified the RNA-binding protein Ataxin-2 as a genetic determinant or risk factor for various diseases including spinocerebellar ataxia type II (SCA2) and amyotrophic lateral sclerosis (ALS), amongst others. Here, we first discuss the increasingly wide-ranging molecular functions of Ataxin-2, from the regulation of RNA stability and translation to the repression of deleterious accumulation of the RNA-DNA hybrid-harbouring R-loop structures. We also highlight the broader physiological roles of Ataxin-2 such as in the regulation of cellular metabolism and circadian rhythms. Finally, we discuss insight from clinically focused studies to shed light on the impact of molecular and physiological roles of Ataxin-2 in various human diseases. We anticipate that deciphering the fundamental functions of Ataxin-2 will uncover unique approaches to help cure or control debilitating and lethal human diseases.

show abstract

Section: Wide-ranging Molecular Functions Of Ataxin-2mentioning

confidence: 99%

Ataxin-2: From RNA Control to Human Health and Disease

Ostrowski

Hall

Mekhail

2017

Genes

View full text Add to dashboard Cite

show abstract

“…Ataxin-2 is one of the polyQ proteins, highly expressed in various neuronal and non-neuronal tissues, including the brain, 45 and has been involved in the regulation of several biological processes such as RNA-mediated metabolism, translation regulation, cytoskeleton reorganization, Ca 2+ homeostasis, and mitochondrial stress. 46 The hallmark of TTR-FAP Val30Met is the presence of extracellular deposits of TTR aggregates and amyloid fibrils in several tissues; particularly, in peripheral nerves, diverse molecular pathways associated with degeneration have been confirmed using in vivo samples and cell culture studies, including activation of nuclear factor kB, proinflammatory cytokines, oxidative stress, and endoplasmic reticulum (ER) stress. 47 Oxidative stress may be further increased by the presence of (CAG) [23][24][25][26][27][28] alleles at the ATXN2 locus and contribute to the processing of misfolded proteins, which in turn cause ER stress with enhanced reactive oxygen species production, thereby creating a feedback loop.…”

Section: Discussionmentioning

confidence: 99%

Large normal alleles of ATXN2 decrease age at onset in transthyretin familial amyloid polyneuropathy Val30Met patients

Santos

Coelho

Alves‐Ferreira

et al. 2019

Annals of Neurology

View full text Add to dashboard Cite

Objective: Transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) is an autosomal dominant neurological disease, caused most frequently by a Val30Met (now classified as Val50Met) substitution in TTR. Age at onset (AO) ranges from 19 to 82 years, and variability exists mostly between generations. Unstable oligonucleotide repeats in various genes are the mechanism behind several neurological diseases, found also to act as modifiers for other disorders. Our aim was to investigate whether large normal repeat alleles of 10 genes had a possible modifier effect in AO in Portuguese TTR-FAP Val30Met families. Methods: We analyzed 329 Portuguese patients from 123 families. Repeat length (at ATXN1, ATXN2, ATXN3, ATXN7, TBP, ATN1, HTT, JPH3, AR, and DMPK) was assessed by single and multiplex polymerase chain reaction, using fluorescently labeled primers, followed by capillary electrophoresis. We used a family-centered approach, and generalized estimating equations were used to account for AO correlation between family members. Results: For ATXN2, the presence of at least 1 allele longer than 22 CAGs was significantly associated with an earlier onset in TTR-FAP Val30Met, decreasing mean AO by 6 years (95% confidence interval = −8.81 to −2.19, p = 0.001). No association was found for the remaining repeat loci. Interpretation: Length of normal repeats at ATXN2 may modify AO in TTR-FAP Val30Met and may function as a risk factor. This can be due to the role of ATXN2 in RNA metabolism and as a modulator of various cellular processes, including mitochondrial stress. This may have relevant implications for prognosis and the follow-up of presymptomatic carriers.

show abstract

“…ATXN2 contains a CAG repeat, initially found to be associated with a class of neuromuscular and neurological disorders, known as polyglutamine disorders, caused by the expansion of the microsatellite repeat within the coding sequence (Al-Chalabi et al, 2012;Lattante et al, 2014). The ATXN2 protein is involved in endocytosis and modulates mTOR signals, critical to maintaining cell growth and survival, thereby modifying translation and mitochondrial function (Carmo-Silva et al, 2017). The N-terminal of this protein contains a polyglutamine tract that generally consists of 14-31 residues that when expanded, can carry up to 200 residues in the pathogenic state (Sproviero et al, 2017).…”

Section: Structural Variants In Alsmentioning

confidence: 99%