Intermediate and Expanded <scp><i>HTT</i></scp> Alleles and the Risk for α‐Synucleinopathies

Pérez-Oliveira, Sergio; Álvarez, Ignacio; Rosas, Irene; Menéndez-González, Manuel; Blázquez-Estrada, Marta; Aguilar, Miquel; Corte, Daniela; Buongiorno, Maríateresa; Molina‐Porcel, Laura; Aldecoa, Ibán; Martı́, Marı́a José; Sánchez‐Juan, Pascual; Infante, Jon; González‐Aramburu, Isabel; García‐González, Pablo; Rosende-Roca, Maiteé; Boada, Merçé; Ruiz, Agustín; Periñán, María Teresa; Macías‐García, Daniel; Muñoz‐Delgado, Laura; Gómez‐Garre, Pilar; Mir, Pablo; Clarimón, Jordi; Lleó, Alberto; Alcolea, Daniel; Casa-Fages, Beatriz De la; Duarte, Israel; Álvarez, Victoria; Pástor, Pau

doi:10.1002/mds.29153

Cited by 7 publications

(9 citation statements)

References 36 publications

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“…However, IAs frequency was increased in the multiple system atrophy (MSA) and MSA carriers with 32 HTT CAG repeats showed isolated polyglutamineQ inclusions in pons and basal nuclei, which are two critical structures in the neurodegeneration of MSA. Besides it had demonstrated the presence of huntingtin‐positive aggregates mainly in the frontal cortex of frontotemporal lobar degeneration (FTLD)‐TDP43 patients with pathological expansions of the HTT gene [ 11 , 14 ].…”

Section: Discussionmentioning

confidence: 99%

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Huntingtin CAG repeats in neuropathologically confirmed tauopathies: Novel insights

Pérez‐Oliveira,

Castilla‐Silgado,

Painous

et al. 2024

Brain Pathology

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Previous studies have suggested a relationship between the number of CAG triplet repeats in the HTT gene and neurodegenerative diseases not related to Huntington's disease (HD). This study seeks to investigate whether the number of CAG repeats of HTT is associated with the risk of developing certain tauopathies and its influence as a modulator of the clinical and neuropathological phenotype. Additionally, it aims to evaluate the potential of polyglutamine staining as a neuropathological screening. We genotyped the HTT gene CAG repeat number and APOE‐ℰ isoforms in a cohort of patients with neuropathological diagnoses of tauopathies (n=588), including 34 corticobasal degeneration (CBD), 98 progressive supranuclear palsy (PSP) and 456 Alzheimer's disease (AD). Furthermore, we genotyped a control group of 1070 patients, of whom 44 were neuropathologic controls. We identified significant differences in the number of patients with pathological HTT expansions in the CBD group (2.7%) and PSP group (3.2%) compared to control subjects (0.2%). A significant increase in the size of the HTT CAG repeats was found in the AD compared to the control group, influenced by the presence of the Apoliprotein E (APOE)‐ℰ4 isoform. Post‐mortem assessments uncovered tauopathy pathology with positive polyglutamine aggregates, with a slight predominance in the neostriatum for PSP and CBD cases and somewhat greater limbic involvement in the AD case. Our results indicated a link between HTT CAG repeat expansion with other non‐HD pathology, suggesting they could share common neurodegenerative pathways. These findings support that genetic or histological screening for HTT repeat expansions should be considered in tauopathies.

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Section: Discussionmentioning

confidence: 99%

“…Recently, a link between the CAG repeats in the HTT gene and frontotemporal dementia/amyotrophic lateral sclero (FTD/ALS) phenotypes has been proposed [ 11 ]. Additionally, we have reported that IAs in HTT can have a role in AD and FTD risk [ 12 , 13 ] and synucleinopathies [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Huntingtin CAG repeats in neuropathologically confirmed tauopathies: Novel insights

Pérez‐Oliveira,

Castilla‐Silgado,

Painous

et al. 2024

Brain Pathology

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“…For instance, both ATXN1 and ATXN2 intermediate expansions are associated with an increased risk of developing amyotrophic lateral sclerosis. 32 HTT intermediate expansions give rise to the risk of multisystem atrophy, 33 and could confer late-onset abnormal motor and cognitive phenotype. 34 Our results suggest that intermediate and pathogenic repeat expansions of these tremor-associated STRs did not increase the risk of familial ET or influence phenotypes of ET patients.…”

Section: Discussionmentioning

confidence: 99%

Tremor-associated short tandem repeat intermediate and pathogenic expansions in familial essential tremor

Zhou,

He,

Zeng

et al. 2024

Brain Communications

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There is an obvious clinical–pathological overlap between essential tremor and some known tremor-associated short tandem repeat expansion disorders. The aim is to analyse whether these short tandem repeat genes, including ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, ATXN8OS, ATXN10, PPP2R2B, TBP, BEAN1, NOP56, DAB1, ATN1, SADM12 and FMR1, are associated with familial essential tremor patients. Genetic analysis of repeat sizes in tremor-associated short tandem repeat expansions was performed in a large cohort of 515 familial essential tremor probands and 300 controls. The demographic and clinical features among carriers of pathogenic expansions, intermediate repeats and non-carriers were compared. A total of 18 out of 515 (18/515, 3.7%) patients were found to have repeats expansions, including 12 cases (12/515, 2.5%) with intermediate repeat expansions (one ATXN1, eight TBP, two FMR1, one ATN1), and six cases (6/515, 1.2%) with pathogenic expansions (one ATXN1, one ATXN2, one ATXN8OS, one PPP2R2B, one FMR1, one SAMD12). There were no statistically significant differences in intermediate repeats compared to healthy controls. Furthermore, there were no significant differences in demographics and clinical features among individuals with pathogenic expansions, intermediate repeat expansions carriers and non-carriers. Our study indicates that the intermediate repeat expansion in tremor-associated short tandem repeat expansions does not pose an increased risk for essential tremor, and rare pathogenic expansion carriers have been found in the familial essential tremor cohort. The diagnosis of essential tremor based solely on clinical symptoms remains a challenge in distinguishing it from known short tandem repeat expansions diseases with overlapping clinical–pathological features.

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“…HD is caused by an abnormal expansion of CAG repeats in the huntingtin gene (HTT) [23]. This critically influences the age of onset and disease severity.…”

Section: Neurodegenerative Diseases-gene Mutationsmentioning

confidence: 99%

Mitochondrial Dynamics in Neurodegenerative Diseases: Unraveling the Role of Fusion and Fission Processes

Grel,

Woznica,

Ratajczak

et al. 2023

IJMS

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Neurodegenerative diseases (NDs) are a diverse group of disorders characterized by the progressive degeneration and death of neurons, leading to a range of neurological symptoms. Despite the heterogeneity of these conditions, a common denominator is the implication of mitochondrial dysfunction in their pathogenesis. Mitochondria play a crucial role in creating biomolecules, providing energy through adenosine triphosphate (ATP) generated by oxidative phosphorylation (OXPHOS), and producing reactive oxygen species (ROS). When they’re not functioning correctly, becoming fragmented and losing their membrane potential, they contribute to these diseases. In this review, we explore how mitochondria fuse and undergo fission, especially in the context of NDs. We discuss the genetic and protein mutations linked to these diseases and how they impact mitochondrial dynamics. We also look at the key regulatory proteins in fusion (MFN1, MFN2, and OPA1) and fission (DRP1 and FIS1), including their post-translational modifications. Furthermore, we highlight potential drugs that can influence mitochondrial dynamics. By unpacking these complex processes, we aim to direct research towards treatments that can improve life quality for people with these challenging conditions.

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Intermediate and Expanded HTT Alleles and the Risk for α‐Synucleinopathies

Cited by 7 publications

References 36 publications

Huntingtin CAG repeats in neuropathologically confirmed tauopathies: Novel insights

Huntingtin CAG repeats in neuropathologically confirmed tauopathies: Novel insights

Tremor-associated short tandem repeat intermediate and pathogenic expansions in familial essential tremor

Mitochondrial Dynamics in Neurodegenerative Diseases: Unraveling the Role of Fusion and Fission Processes

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