ATXN2 intermediate repeat expansions influence the clinical phenotype in frontotemporal dementia

Rubino, Elisa; Mancini, Cecilia; Boschi, Silvia Regina Matos da Silva; Ferrero, P.; Ferrone, Marina; Bianca, Stefano; Zucca, Milena; Orsi, Laura; Pinessi, Lorenzo; Govone, Flora; Vacca, Alessandro; Gai, Annalisa; Giordana, Maria Teresa; Brusco, Alfredo; Rainero, Innocenzo

doi:10.1016/j.neurobiolaging.2018.09.009

Cited by 26 publications

(25 citation statements)

References 9 publications

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“…In model organisms such as yeast, flies and mice it was shown that ATXN2 depletion by genetic knockout or mRNA-knockdown protects against the neurotoxicity of TDP43, which causes motor neuron degeneration in ALS and in FTLD. In addition, patient studies showed genetic ATXN2 variants to contribute to the risk of ALS/FTLD [12, 44, 58, 94, 99, 170]. Although the molecular mechanisms of ALS/FTLD are not understood, the crucial role of RNA toxicity in its pathogenesis became plain upon the identification of various ALS/FTLD disease genes, such as the RNA binding proteins TDP43 (encoded by the TARDBP gene), FUS, HNRNPA2B1, the RNA-particle transporting KIF5A, the RNA toxicity sensor RIPK1, and other stress response factors such as GRN and SOD1 [200].…”

Section: Introductionmentioning

confidence: 99%

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Canet-Pons

Sen

Arsovic

et al. 2019

Preprint

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Large polyglutamine expansions in Ataxin-2 (ATXN2) cause multi-system nervous atrophy in Spinocerebellar Ataxia type 2 (SCA2). Intermediate size expansions carry a risk for selective motor neuron degeneration, known as Amyotrophic Lateral Sclerosis (ALS). Conversely, the depletion of ATXN2 prevents disease progression in ALS. Although ATXN2 interacts directly with RNA, and in ALS pathogenesis there is a crucial role of RNA toxicity, the affected functional pathways remain ill defined. Here, we examined an authentic SCA2 mouse model with Atxn2-CAG100-KnockIn for a first definition of molecular mechanisms in spinal cord pathology.Neurophysiology of lower limbs detected sensory neuropathy rather than motor denervation. Triple immunofluorescence demonstrated cytosolic ATXN2 aggregates sequestrating TDP43 and TIA1 from the nucleus. In immunoblots, this was accompanied by elevated CASP3, RIPK1 and PQBP1 abundance. RT-qPCR showed increase of Grn, Tlr7 and Rnaset2 mRNA versus Eif5a2, Dcp2, Uhmk1 and Kif5a decrease. These SCA2 findings overlap well with known ALS features. Similar to other ataxias and dystonias, decreased mRNA levels for Unc80, Tacr1, Gnal, Ano3, Kcna2, Elovl5 and Cdr1 contrasted with Gpnmb increase. Preterminal stage tissue showed strongly activated microglia containing ATXN2 aggregates, with parallel astrogliosis. Global transcriptome profiles from stages of incipient motor deficit versus preterminal age identified molecules with progressive downregulation, where a cluster of cholesterol biosynthesis enzymes including Dhcr24, Msmo1, Idi1and Hmgcs1 was prominent. Gas chromatography demonstrated a massive loss of crucial cholesterol precursor metabolites. Overall, the ATXN2 protein aggregation process affects diverse subcellular compartments, in particular stress granules, endoplasmic reticulum and receptor tyrosine kinase signaling. These findings identify new targets and potential biomarkers for neuroprotective therapies. Introduction:Within the dynamic research field into neurodegenerative disorders, the rare monogenic variant SCA2 (Spinocerebellar Ataxia type 2) gained much attention over the past decade, since its pathogenesis is intertwined with the motor neuron diseases ALS/FTLD (Amyotrophic Lateral Sclerosis / Fronto-Temporal Lobar Dementia) and with extrapyramidal syndromes such as Parkinson/PSP (Progressive Supranuclear Palsy). Particularly in the past year, it received massive interest since antisense-oligonucleotides were shown to effectively prevent the disease in mouse models, with clinical trials now being imminent. Still, there is an urgent unmet need to define the molecular events of pathogenesis and to identify biomarkers of progression in SCA2 patients, which reflect therapeutic benefits much more rapidly than clinical rating scales, brain imaging volumetry or neurophysiology measures.SCA2 was first described as separate entity in Indian patients, based on the characteristic early slowing of eye saccadic movements [222]. A molecularly homogeneous founder population of ~1,000 patients in...

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Section: Introductionmentioning

confidence: 99%

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Canet-Pons

Sen

Arsovic

et al. 2019

Preprint

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“…This observation indicates that ATXN2 is involved in the formation of TDP-43 aggregates at least in part, possibly causing acceleration of neurodegeneration as well. Consistent with this notion, genetic alteration of ATXN2 as intermediate CAG repeat expansions was reported to exacerbate the disease onset and clinical phenotype of FTLD [ 36 ]. These findings suggest that ATXN2 is involved in pathogenesis of the disease through toxic gain of function mechanisms.…”

Section: Discussionmentioning

confidence: 84%

“…Although the contribution of ATXN2 to TDP-43 proteinopathies has been studied mostly in ALS, recent studies reported the pathogenic role of ATXN2 in FTLD as a phenotypic modifier. Rubino et al reported the association between ATXN2 intermediate repeat expansions and an earlier age at onset, parkinsonism and psychotic symptoms in the initial phase of FTLD [ 36 ]. Lattante et al reported that ATXN2 intermediate repeat expansions are a strong risk factor not only in ALS but also in FTLD-ALS, and could act as a strong modifier of the FTLD phenotype in the presence of C9orf72 repeat expansion [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Intracellular dynamics of Ataxin-2 in the human brains with normal and frontotemporal lobar degeneration with TDP-43 inclusions

Watanabe

Higashi

Nonaka

et al. 2020

acta neuropathol commun

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TAR DNA-binding protein of 43 kDa (TDP-43) is a major component of intracellular aggregates formed in brains of the patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), which are correctively referred to as TDP-43 proteinopathies. A link between Ataxin-2 (ATXN2) and TDP-43 proteinopathies was established when intermediate CAG repeat expansions of ATXN2 gene were found to be associated with ALS and it was shown that ATXN2 modifies TDP-43 toxicity. Although ATXN2’s contribution to TDP-43 proteinopathies has been mostly studied in ALS, recent studies have shown that intermediate repeat expansions of ATXN2 also influence the phenotype of FTLD by an unknown mechanism. To address this issue, we immunohistochemically and biochemically analyzed the intracellular dynamics of ATXN2 in brains of normal controls and FTLD-TDP cases. The immunohistochemical studies revealed that ATXN2 localized in the neuronal cytoplasm and proximal dendrites, and expressed widely and uniformly in normal human brains. A semi-quantitative immunofluorescent analysis of normal brains revealed that the cytoplasmic ATXN2 strongly associates with ribosomal protein S6 and poly-A binding protein 1 and partially overlaps with the endoplasmic reticulum marker Calnexin, suggesting a major role of ATXN2 in protein synthesis. The results of immunohistochemical and biochemical analyses of brains from FTLD-TDP cases showed the colocalization of ATXN2 and phosphorylated TDP-43 in the dystrophic neurites and the neuronal cytoplasmic inclusions in the hippocampal region, and a significant reduction of ATXN2 protein compared to controls. These results suggest that ATXN2 is involved in the pathological process of FTLD-TDP. It remains to be clarified whether reduced ATXN2 expression induces neurodegeneration by impairing protein synthesis or plays a neuroprotective role by attenuating the toxicity of TDP-43 aggregates in FTLD-TDP and other TDP-43 proteinopathies.

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“…Subsequently, ATXN2 CAG repeats of ≥29 were also found to be associated with ALS and familial ALS-FTD but not sporadic ALS-FTD or FTD (Lattante et al, 2014). A further study of 368 cases also found no significant correlation between FTD and ATXN2 CAG repeat size though they did find that intermediate repeats (≥27) were associated with an earlier age at onset of FTD (Rubino et al, 2019).…”

Section: Als13: Ataxin 2 (Atxn2)mentioning

confidence: 95%

Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia

et al. 2020

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ATXN2 intermediate repeat expansions influence the clinical phenotype in frontotemporal dementia

Cited by 26 publications

References 9 publications

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Intracellular dynamics of Ataxin-2 in the human brains with normal and frontotemporal lobar degeneration with TDP-43 inclusions

Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia

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