ATXN-2 CAG repeat expansions are interrupted in ALS patients

Corrado, Lucia; Mazzini, Letizia; Oggioni, Gaia Donata; Luciano, Bernadetta; Godi, Michela; Brusco, Alfredo; D’Alfonso, Sandra

doi:10.1007/s00439-011-1000-2

Cited by 54 publications

(50 citation statements)

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“…20 Because of the presence of TDP-43 inclusions in many neurodegenerative diseases and the heterogeneity of their clinical presentation, a number of studies have evaluated ATXN2 repeat sizes in patients with neurodegenerative diseases. 17,[21][22][23][24][25][26][27][28][29][30][31][32][33] All the studies confirmed a significant association between intermediary repeat lengths and ALS, which is even stronger when familial cases are considered separately from sporadic cases. An association has also been found with PSP.…”

Section: Figurementioning

confidence: 70%

Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders

et al. 2014

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Objective: The aim of this study was to establish the frequency of ATXN2 polyglutamine (polyQ) expansion in large cohorts of patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), and to evaluate whether ATXN2 could act as a modifier gene in patients carrying the C9orf72 expansion.Methods: We screened a large cohort of French patients (1,144 ALS, 203 FTD, 168 FTD-ALS, and 109 PSP) for ATXN2 CAG repeat length. We included in our cohort 322 carriers of the C9orf72 expansion (202 ALS, 63 FTD, and 57 FTD-ALS).Results: We found a significant association with intermediate repeat size ($29 CAG) in patients with ALS (both familial and sporadic) and, for the first time, in patients with familial FTD-ALS. Of interest, we found the co-occurrence of pathogenic C9orf72 expansion in 23.2% of ATXN2 intermediate-repeat carriers, all in the FTD-ALS and familial ALS subgroups. In the cohort of C9orf72 carriers, 3.1% of patients also carried an intermediate ATXN2 repeat length. ATXN2 repeat lengths in patients with PSP and FTD were found to be similar to the controls.Conclusions: ATXN2 intermediary repeat length is a strong risk factor for ALS and FTD-ALS.Furthermore, we propose that ATXN2 polyQ expansions could act as a strong modifier of the FTD phenotype in the presence of a C9orf72 repeat expansion, leading to the development of clinical signs featuring both FTD and ALS. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are considered part of a spectrum of neurologic diseases because they share pathologic hallmarks, consisting of TAR DNA-binding protein 43 (TDP-43) pathology, and a similar genetic background, including C9orf72 expansion. On the other hand, FTD shares a prominent frontal cognitive syndrome and parkinsonism signs with progressive supranuclear palsy (PSP). Spinocerebellar ataxia type 2 (SCA2), characterized by cerebellar ataxia, parkinsonism, and mild dementia, is caused by an expanded CAG trinucleotide repeat encoding for a polyglutamine (polyQ) tract in ataxin-2 protein (ATXN2; OMIM: *601517). A link between SCA2 and ALS was established in 2010, when ATXN2 intermediate-length expansions were found to be significantly associated with ALS and it was shown that ATXN2 protein modifies TDP-43 toxicity.1 In this study, we analyzed the size of ATXN2 repeats in a large French cohort of 1,624 patients with ALS, FTD, FTD-ALS, and PSP to evaluate the exact contribution of the ATXN2 repeat size to

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Section: Figurementioning

confidence: 70%

Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders

et al. 2014

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“…6,8,12 Normal ATXN-2 alleles were in fact #31 repeats in several studies. 5,6,8 In our sALS cohort from southern Italy, we found a significant association with ATXN-2 when PolyQ repeats were $28 (2.7% alleles), with only 0.5% expanded alleles in controls. This makes our finding closer to the study of the American and Chinese ALS cohorts, where the disease was shown to be associated with ATXN-2 repeat expansions 27-33 and $27, respectively.…”

Section: Resultsmentioning

confidence: 97%

“…[5][6][7][8][9][10][11][12] The finding that ATXN-1 PolyQ repeats $32 also represent a risk factor for ALS is novel, and suggests that intermediate expansions of both ataxins might indeed be involved in the pathogenesis of this neurodegenerative disorder.…”

Section: Resultsmentioning

confidence: 99%

“…5 This finding led to a number of studies from America, Europe, and China that have now demonstrated that ATXN-2 intermediate poly-CAG expansions with CAA interruptions are indeed a risk factor for ALS. [5][6][7][8][9][10][11][12] This effect appears to be specific, as ATXN-2 repeat length intermediate expansions in Alzheimer disease, Parkinson disease, and frontotemporal degeneration were not significantly more frequent than in controls. …”

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confidence: 91%

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Ataxin-1 and ataxin-2 intermediate-length PolyQ expansions in amyotrophic lateral sclerosis

et al. 2012

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Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder of motor neurons, leading to a severe muscle weakness and atrophy. 1 Several mutated genes (e.g., Cu/Zn SOD1, FUS/TLS, TARDBP, C9ORF72) have been demonstrated to be implicated in the disease. [1][2][3][4] A recent work demonstrated that TDP-43, a TARDBP gene product, and ataxin-2 (ATXN-2) form a complex that depends on RNA binding and that a small number of patients with ALS are carriers of ATXN-2 intermediate expansions (27-33 glutamines). 5 This finding led to a number of studies from America, Europe, and China that have now demonstrated that ATXN-2 intermediate poly-CAG expansions with CAA interruptions are indeed a risk factor for ALS. [5][6][7][8][9][10][11][12] This effect appears to be specific, as ATXN-2 repeat length intermediate expansions in Alzheimer disease, Parkinson disease, and frontotemporal degeneration were not significantly more frequent than in controls. 13Clinical signs and symptoms of motor neuron degeneration, with bulbar and distal neurogenic muscle atrophy, have been described in spinocerebellar ataxias. [14][15][16] In particular, the protein product of spinocerebellar ataxia 1 (SCA1), ataxin-1 (ATXN-1), forms aggregates in the nucleus and binds to coiled bodies, exerting a toxic effect on RNA metabolism, thus leading to neuron degeneration including motor neurons.

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“…Maya modelinde, SCA2 ile ilişkilendirilmiş ataksin-2 proteininin ortologu olan Pbp1'in, TDP-43 aşırı üretimine bağlı toksisiteyi düzenlediğinin görülmesi üzerine ALS hastalarında yapılan çalışmalar, ataksin-2'nin ALS oluşumu için bugüne kadar bulunmuş en önemli risk faktörü olduğunu göstermiştir. Ataksin-2 ve TDP-43'ün etkileşim mekanizması henüz netlik kazanmamıştır (74)(75)(76)(77)(78)(79)(80)(81).…”

Section: Tdp-43 Ve Model Sistemlerunclassified

TDP-43 Proteinopatileri: Nörodejeneratif Konformasyon Bozukluğu Hastalıklarında Yeni Bir Oyuncu

Lahut¹,

Özeş²,

Agar³

et al. 2012

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ÖzetHücredeki proteinlerin toplamına proteom, proteomun hücre içindeki stabil durumuna proteostaz denilir. Proteostazın korunması için, proteinlerin doğru konsantrasyonu, hatasız ekspresyonu, düzgün üç-boyutlu katlanması, translokasyonu ve gerekli durumlarda yıkımı sağlanmalıdır. Genetik ve çevresel faktörler sonucu proteinlerin yanlış katlanma ve agregasyona-yatkın bir konformasyona dönüşmesi, hücre stresini artırır. Birçok kanıt, hasarlı protein birikiminin, sadece hücre-içi süreçlerin verimliliği ve hassasiyetine doğrudan olumsuz etki yapmakla kalmadığını, düzeltilmedikleri takdirde, işlev bozukluğu şelalesini tetikleyerek, proteinopatiler olarak adlandırılan bir dizi protein konformasyonu bozukluğu hastalığına neden olduğunu göstermektedir. Günümüzde özellikle yaşlı popülasyon oranları yüksek, gelişmiş toplumları tehdit eden, Alzheimer Hastalığı ( Sum maryThe proteome is the sum of all proteins inside a cell, and proteostasis (protein homeostasis) is the stable condition of the proteome. Proteostasis is essential for the cellular and organismal health. Stress, aging and the chronic expression of misfolded proteins challenge the proteostasis machinery and the vitality of the cell. There is increasing evidence that the accumulation of damaged proteins not only has direct consequences on the efficiency and fidelity of cellular processes but also, when not corrected, that they initiate a cascade of dysfunction, which in humans is associated with a plethora of diseases of protein conformation, referred to as proteinopathies. Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), cancer and diabetes, whose frequencies have drastically increased in countries with aging populations, are all consequences of misfolded proteins. This paper focuses on TDP-43, which excelled as a key protein in neurodegenerative processes because of its association with different diseases, especially with ALS and Frontotemporal Lobar Dementia (FTLD), the two best studied examples of TDP-43 proteinopathies (Turkish Journal of Neurology 2012; 18:1-10) Key Words: TDP-43, neurodegeneration, protein folding, aggregation, ALS, FTLD, model systems Giriş Proteom, Proteostaz ve Protein KatlanmasıBir hücrenin tüm proteinlerinin toplamına proteom denir. Proteomun işlevini hatasız bir şekilde yerine getirmesi, hücresel süreçler için en temel şartlardan biridir ve canlı organizmaların oluşumları ve yaşamlarını sağlıklı bir şekilde sürdürmeleri için büyük önem taşır. Tüm hücrelerde, proteomun hatasız bir şekilde işlemesinden, şaperon, transport molekülleri, ubikitin-temelli proteozom ve otofajik sistem gibi karmaşık yapıları barındıran moleküler bir ağ sorumludur (1-7).

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ATXN-2 CAG repeat expansions are interrupted in ALS patients

Cited by 54 publications

References 20 publications

Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders

Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders

Ataxin-1 and ataxin-2 intermediate-length PolyQ expansions in amyotrophic lateral sclerosis

TDP-43 Proteinopatileri: Nörodejeneratif Konformasyon Bozukluğu Hastalıklarında Yeni Bir Oyuncu

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