Differential Regulation of Tau Exon 2 and 10 Isoforms in Huntington’s Disease Brain

Pétry, Séréna; Nateghi, Behnaz; Keraudren, Rémi; Sergeant, Nicolas; Planel, Emmanuel; Hébert, Sébastien S.; St‐Amour, Isabelle

doi:10.1016/j.neuroscience.2022.07.014

Cited by 11 publications

(5 citation statements)

References 43 publications

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“… 64 Second, the aging brain of rhesus macaques (Old World monkeys) is much more vulnerable to neurotoxicity upon induction of pathological amyloid-β protein than that of marmosets (New World monkeys) and rats; this vulnerability is evident in the presence of amyloid β plaques and hyperphosphorylated tau. 65 In addition, individual or coordinated alterations of exons 2, 3, and 10 splicing have been reported in postmortem brains of AD, PSP, and HD patients (e.g., several articles 28 , 66 , 67 and references therein). These data support that tau has acquired intrinsic functional differences during evolution, leading to distinct disease susceptibilities in different species.…”

Section: Discussionmentioning

confidence: 99%

Lineage-specific splicing regulation of MAPT gene in the primate brain

Recinos,

Bao,

Wang

et al. 2024

Cell Genomics

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Section: Discussionmentioning

confidence: 99%

Lineage-specific splicing regulation of MAPT gene in the primate brain

Recinos,

Bao,

Wang

et al. 2024

Cell Genomics

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“…In addition, it has been described that MAPT exon 10 improves the ability of Tau to bound microtubules and favor their polymerization [ 56 , 57 ], thus MAPT isoform-lacking exon 10 would interfere in MIO-M1 SCA7 model with microtubules polymerization affecting the cytoskeleton dynamics. Interestingly, augmentation of tau exon 10 inclusion was reported in the cortex and putamen of HD samples [ 58 ], suggesting that this splicing event may be relevant in the context of polyQ diseases. Furthermore, abnormal splicing at exon 10 is sufficient to cause neurodegeneration [ 59 , 60 ].…”

Section: Discussionmentioning

confidence: 99%

RNA Foci Formation in a Retinal Glial Model for Spinocerebellar Ataxia Type 7

Suárez-Sánchez

Ávila-Avilés

Sanchez-Celis

et al. 2022

Life

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Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder characterized by cerebellar ataxia and retinopathy. SCA7 is caused by a CAG expansion in the ATXN7 gene, which results in an extended polyglutamine (polyQ) tract in the encoded protein, the ataxin-7. PolyQ expanded ataxin-7 elicits neurodegeneration in cerebellar Purkinje cells, however, its impact on the SCA7-associated retinopathy remains to be addressed. Since Müller glial cells play an essential role in retinal homeostasis, we generate an inducible model for SCA7, based on the glial Müller MIO-M1 cell line. The SCA7 pathogenesis has been explained by a protein gain-of-function mechanism, however, the contribution of the mutant RNA to the disease cannot be excluded. In this direction, we found nuclear and cytoplasmic foci containing mutant RNA accompanied by subtle alternative splicing defects in MIO-M1 cells. RNA foci were also observed in cells from different lineages, including peripheral mononuclear leukocytes derived from SCA7 patient, suggesting that this molecular mark could be used as a blood biomarker for SCA7. Collectively, our data showed that our glial cell model exhibits the molecular features of SCA7, which makes it a suitable model to study the RNA toxicity mechanisms, as well as to explore therapeutic strategies aiming to alleviate glial dysfunction.

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“…Hence, therapeutic approaches for the treatment of HD besides targeting HTT comprise targeting of TAU similar to AD, including modulation of MAPT gene expression, inhibition of TAU aggregation, targeting hyperphosphorylated TAU, and TAU immunotherapies [ 219 ]. Differential regulation of MAPT exons 2, 3 and 10 was observed in various brain regions in HD [ 220 ]. An imbalance of TAU isoforms (especially the 4R/3R ratio) in favor of the 4R isoform due to altered MAPT splicing (increased exon 10 inclusion) is reported in HD similar to a subset of primary tauopathies.…”

Section: Secondary Tauopathiesmentioning

confidence: 99%

Genetic forms of tauopathies: inherited causes and implications of Alzheimer’s disease-like TAU pathology in primary and secondary tauopathies

Langerscheidt,

Wied,

Al Kabbani

et al. 2024

J Neurol

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Tauopathies are a heterogeneous group of neurologic diseases characterized by pathological axodendritic distribution, ectopic expression, and/or phosphorylation and aggregation of the microtubule-associated protein TAU, encoded by the gene MAPT. Neuronal dysfunction, dementia, and neurodegeneration are common features of these often detrimental diseases. A neurodegenerative disease is considered a primary tauopathy when MAPT mutations/haplotypes are its primary cause and/or TAU is the main pathological feature. In case TAU pathology is observed but superimposed by another pathological hallmark, the condition is classified as a secondary tauopathy. In some tauopathies (e.g. MAPT-associated frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Alzheimer's disease (AD)) TAU is recognized as a significant pathogenic driver of the disease. In many secondary tauopathies, including Parkinson's disease (PD) and Huntington's disease (HD), TAU is suggested to contribute to the development of dementia, but in others (e.g. Niemann-Pick disease (NPC)) TAU may only be a bystander. The genetic and pathological mechanisms underlying TAU pathology are often not fully understood. In this review, the genetic predispositions and variants associated with both primary and secondary tauopathies are examined in detail, assessing evidence for the role of TAU in these conditions. We highlight less common genetic forms of tauopathies to increase awareness for these disorders and the involvement of TAU in their pathology. This approach not only contributes to a deeper understanding of these conditions but may also lay the groundwork for potential TAU-based therapeutic interventions for various tauopathies.

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Differential Regulation of Tau Exon 2 and 10 Isoforms in Huntington’s Disease Brain

Cited by 11 publications

References 43 publications

Lineage-specific splicing regulation of MAPT gene in the primate brain

Lineage-specific splicing regulation of MAPT gene in the primate brain

RNA Foci Formation in a Retinal Glial Model for Spinocerebellar Ataxia Type 7

Genetic forms of tauopathies: inherited causes and implications of Alzheimer’s disease-like TAU pathology in primary and secondary tauopathies

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