Role for ATXN1, ATXN2, and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease

Rosas, Irene; Martı́nez, Carmen; Clarimón, Jordi; Lleó, Alberto; Illán-Gala, Ignacio; Dols‐Icardo, Oriol; Borroni, Barbara; Almeida, Maria Rosário; Zee, Julie van der; Broeckhoven, Christine Van; Bruni, Amalia C.; Anfossi, Maria; Bernardi, Livia; Maletta, Raffaele; Serpente, María; Galimberti, Daniela; Scarpini, Elio; Rossi, Giacomina; Caroppo, Paola; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Nacmias, Benedetta; Sorbi, Sandro; Piaceri, Irene; Bagnoli, Silvia; Antonell, Anna; Sánchez‐Valle, Raquel; Casa-Fages, Beatriz De la; Grandas, Francisco; Díez-Fairén, Mónica; Pástor, Pau; Ferrari, Raffaele; Álvarez, Victoria; Menéndez-González, Manuel

doi:10.1016/j.neurobiolaging.2019.10.017

Cited by 44 publications

(35 citation statements)

References 44 publications

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“…CAA interrupted repeat expansions of SCA2 length can present with parkinsonism ( 36 , 56 ), which is a movement disorder characterized by tremors and stiffness. Interrupted expansions have also been associated with FTD ( 35 ). These different disease presentations reflect the varying extent to which different brain regions are affected, with differing penetrance of functional loss in different brain regions presumably underlying symptomatic presentation of ataxia versus motor neuron degeneration versus parkinsonism versus dementia as the dominant feature.…”

Section: Discussionmentioning

confidence: 99%

Toxicity of pathogenic ataxin-2 in Drosophila shows dependence on a pure CAG repeat sequence

McGurk

Rifai

Shcherbakova

et al. 2021

Human Molecular Genetics

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Spinocerebellar ataxia type 2 is a polyglutamine (polyQ) disease associated with an expanded polyQ domain within the protein product of the ATXN2 gene. Interestingly, polyQ repeat expansions in ATXN2 are also associated with amyotrophic lateral sclerosis (ALS) and parkinsonism depending upon the length of the polyQ repeat expansion. The sequence encoding the polyQ repeat also varies with disease presentation: a pure CAG repeat is associated with SCA2, whereas the CAG repeat in ALS and parkinsonism is typically interrupted with the glutamine encoding CAA codon. Here we asked if the purity of the CAG sequence encoding the polyQ repeat in ATXN2 could impact the toxicity of the ataxin-2 protein in vivo in Drosophila. We found that ataxin-2 encoded by a pure CAG repeat conferred toxicity in the retina and nervous system, whereas ataxin-2 encoded by a CAA-interrupted repeat or CAA-only repeat failed to confer toxicity, despite expression of the protein at similar levels. Furthermore, the CAG-encoded ataxin-2 protein aggregated in the fly eye, while ataxin-2 encoded by either a CAA/G or CAA repeat remained diffuse. The toxicity of the CAG-encoded ataxin-2 protein was also sensitive to the translation factor eIF4H, a known modifier of the toxic GGGGCC repeat in flies. These data indicate that ataxin-2 encoded by a pure CAG vs interrupted CAA/G polyQ repeat domain is associated with differential toxicity, indicating that mechanisms associated with the purity of the sequence of the polyQ domain contribute to disease.

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Section: Discussionmentioning

confidence: 99%

Toxicity of pathogenic ataxin-2 in Drosophila shows dependence on a pure CAG repeat sequence

McGurk

Rifai

Shcherbakova

et al. 2021

Human Molecular Genetics

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“…Nevertheless, HTT CAG repeats below the disease threshold have been showed to play a vital role in evolution and intelligence [22]. More recently, CAG repeats in the intermediate range have been linked to depression [23][24][25], AD [26], and the non-fluent variant of primary progressive aphasia [27].…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, subjects carrying IAs experienced more depressive symptoms compared to control subjects [23][24][25]. Other studies reported a significantly higher frequency of HTT IAs in AD patients [26] and in the non-fluent variant of primary progressive aphasia [27], suggesting a role of the HTT gene in the pathogenesis of these diseases. Whether HTT CAG repeats also influence cognition in preclinical and in prodromic phases of AD has not been explored.…”

Section: Introductionmentioning

confidence: 91%

The Effect of CAG Repeats within the Non-Pathological Range in the HTT Gene on Cognitive Functions in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment

et al. 2021

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The Huntingtin gene (HTT) is within a class of genes containing a key region of CAG repeats. When expanded beyond 39 repeats, Huntington disease (HD) develops. Individuals with less than 35 repeats are not associated with HD. Increasing evidence has suggested that CAG repeats play a role in modulating brain development and brain function. However, very few studies have investigated the effect of CAG repeats in the non-pathological range on cognitive performances in non-demented individuals. In this study, we aimed to test how CAG repeats’ length influences neuropsychological scores in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). We included 75 patients (46 SCD and 29 MCI). All patients underwent an extensive neuropsychological battery and analysis of HTT alleles to quantify the number of CAG repeats. Results: CAG repeat number was positively correlated with scores of tests assessing for executive function, visual–spatial ability, and memory in SCD patients, while in MCI patients, it was inversely correlated with scores of visual–spatial ability and premorbid intelligence. When we performed a multiple regression analysis, we found that these relationships still remained, also when adjusting for possible confounding factors. Interestingly, logarithmic models better described the associations between CAG repeats and neuropsychological scores. CAG repeats in the HTT gene within the non-pathological range influenced neuropsychological performances depending on global cognitive status. The logarithmic model suggested that the positive effect of CAG repeats in SCD patients decreases as the number of repeats grows.

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“…ATXN2 intermediate alleles lowers AO in frontotemporal dementia (FTD) [ 25 ], in addition, those patients had parkinsonism and psychotic symptoms at the time of disease onset [ 25 ]. Intermediate alleles are overrepresented also in Alzheimer's disease and behavioral FTD suggesting a potential link between ATXN2 with tauopathies [ 26 ].…”

Section: Spinocerebellar Ataxia 2 Mutagenesis and Founder Effectsmentioning

confidence: 99%

Ataxin-2 gene: a powerful modulator of neurological disorders

Laffita-Mesa

Paucar

Svenningsson

2021

Current Opinion in Neurology

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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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Role for ATXN1, ATXN2, and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease

Cited by 44 publications

References 44 publications

Toxicity of pathogenic ataxin-2 in Drosophila shows dependence on a pure CAG repeat sequence

Toxicity of pathogenic ataxin-2 in Drosophila shows dependence on a pure CAG repeat sequence

The Effect of CAG Repeats within the Non-Pathological Range in the HTT Gene on Cognitive Functions in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment

Ataxin-2 gene: a powerful modulator of neurological disorders

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