Phosphorylated and aggregated TDP-43 with seeding properties are induced upon mutant Huntingtin (mHtt) polyglutamine expression in human cellular models

Coudert, Laurent; Nonaka, Takashi; Bernard, Emilien; Hasegawa, Masato; Schaeffer, Laurent; Leblanc, Pascal

doi:10.1007/s00018-019-03059-8

Cited by 28 publications

(27 citation statements)

References 70 publications

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“…We could show that phosphorylation of S409/S410 in TDP-43 is increased and that TDP-43 colocalises with ATXN7 aggregates in SCA7 cells. This is consistent with previous studies identifying increased TDP-43 phosphorylation and sequestration in SCA7 mice and patients, as well as in several other neurodegenerative diseases [37][38][39][40][41]34]. Findings in other diseases have indicated that TDP-43 exits the nucleus during stress, [42,27] and that TDP-43 phosphorylation exacerbates TDP-43 related neuropathology [35,43].…”

Section: Discussionsupporting

confidence: 92%

“…Hyperphosphorylated TDP-43 has previously been observed in cell culture during polyglutamine expression [32], as well as in several other neurodegenerative diseases [33,34], and has been identi ed as a pathological marker [35]. Therefore, we wanted to investigate if TDP-43 hyperphosphorylation occurred in our SCA7 cell model as well.…”

Section: Tdp-43 Is Hyperphosphorylated In Atxn7q65 Induced Cellsmentioning

confidence: 96%

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Key Modulators of the Stress Granule Response TIA1, TDP-43, and G3BP1 are Altered by Polyglutamine Expanded ATXN7

Niss

Piñero-Paez

Zaidi

et al. 2022

Preprint

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Spinocerebellar ataxia type ATXN7 (SCA7) and other polyglutamine (polyQ) diseases are caused by expansions of polyQ repeats in disease specific proteins. Aggregation of the polyQ proteins resulting in various forms of cellular stress, that could induce the stress granule (SG) response, is believed to be a common pathological mechanism in these disorders. SGs can contribute to cell survival, but have also been suggested to exacerbate disease pathology by seeding protein aggregation. In this study, we show that two SG related proteins, TDP-43 and TIA1, are sequestered into the aggregates formed by polyQ expanded ATXN7 in SCA7 cells. Interestingly, mutant ATXN7 also localises to induced SGs and this association altered the shape of the SGs. In spite of this, neither the ability to induce nor disassemble SGs, in response to arsenite stress induction or relief, was affected in SCA7 cells. Moreover, we could only detect a small, non-significant, increase in ATXN7 aggregation following SG induction. However, mutant ATXN7 expression in itself increased the speckling of the SG nucleating protein G3BP1 and the SG response. Taken together, our results indicate that the SG response is induced, and although some key modulators of SGs show altered behaviour, the dynamics appear normal in the presence of mutant ATXN7.

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Section: Discussionsupporting

confidence: 92%

Section: Tdp-43 Is Hyperphosphorylated In Atxn7q65 Induced Cellsmentioning

confidence: 96%

Key Modulators of the Stress Granule Response TIA1, TDP-43, and G3BP1 are Altered by Polyglutamine Expanded ATXN7

Niss

Piñero-Paez

Zaidi

et al. 2022

Preprint

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“…RNA-binding proteins that localize in SGs such as TIA-1, TDP-43, and G3BP1 have been observed in pathological aggregates of neurodegenerative diseases like Alzheimer’s, Huntington’s and ALS. These findings suggest that SG dysregulation might have a role in protein aggregate formation in neurodegeneration ( Ash et al, 2014 ; Vanderweyde et al, 2016 ; McAleese et al, 2017 ; St-Amour et al, 2018 ; Coudert et al, 2019 ; Ryan and Fawzi, 2019 ; Wolozin and Ivanov, 2019 ; Dudman and Qi, 2020 ).…”

Section: Stress Granules As Therapeutic Targets In Rna Virus Infection Cancer and Neurodegenerationmentioning

confidence: 86%

The Integral Role of RNA in Stress Granule Formation and Function

Campos-Melo

Hawley

Droppelmann

et al. 2021

Front. Cell Dev. Biol.

100

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Stress granules (SGs) are phase-separated, membraneless, cytoplasmic ribonucleoprotein (RNP) assemblies whose primary function is to promote cell survival by condensing translationally stalled mRNAs, ribosomal components, translation initiation factors, and RNA-binding proteins (RBPs). While the protein composition and the function of proteins in the compartmentalization and the dynamics of assembly and disassembly of SGs has been a matter of study for several years, the role of RNA in these structures had remained largely unknown. RNA species are, however, not passive members of RNA granules in that RNA by itself can form homo and heterotypic interactions with other RNA molecules leading to phase separation and nucleation of RNA granules. RNA can also function as molecular scaffolds recruiting multivalent RBPs and their interactors to form higher-order structures. With the development of SG purification techniques coupled to RNA-seq, the transcriptomic landscape of SGs is becoming increasingly understood, revealing the enormous potential of RNA to guide the assembly and disassembly of these transient organelles. SGs are not only formed under acute stress conditions but also in response to different diseases such as viral infections, cancer, and neurodegeneration. Importantly, these granules are increasingly being recognized as potential precursors of pathological aggregates in neurodegenerative diseases. In this review, we examine the current evidence in support of RNA playing a significant role in the formation of SGs and explore the concept of SGs as therapeutic targets.

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“…The interaction of m htt and tau splicing factor SRSF6 may cause an imbalance between tau isoforms (4R 53R). m htt decreases PP2B (calcineurin) levels, promoting tau hyperphosphorylation (p-tau) [ 87 , 88 ].…”

Section: Mechanisms Of Pathogenesis In Hdmentioning

confidence: 99%

Huntington disease: Advances in the understanding of its mechanisms

Gatto

Rojas

Persi

et al. 2020

Clinical Parkinsonism & Related Disorders

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Huntington disease (HD) is a devastating monogenic autosomal dominant disorder. HD is caused by a CAG expansion in exon 1 of the gene coding for huntingtin, placed in the short arm of chromosome 4. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. Here, we review some of the currently known functions of the wild-type huntingtin protein and discuss the deleterious effects that arise from the expansion of the CAG repeats, which are translated into an abnormally long polyglutamine tract. Also, we present a modern view on the molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. The main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as autophagy, impaired mitochondrial biogenesis, lysosomal dysfunction, organelle and protein transport, inflammation, oxidative stress, and transcription factor modulation. However, other unraveling mechanisms are still unknown. This practical and brief review summarizes some of the currently known functions of the wild-type huntingtin protein and the recent findings related to the mechanisms involved in HD pathogenesis.

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Phosphorylated and aggregated TDP-43 with seeding properties are induced upon mutant Huntingtin (mHtt) polyglutamine expression in human cellular models

Cited by 28 publications

References 70 publications

Key Modulators of the Stress Granule Response TIA1, TDP-43, and G3BP1 are Altered by Polyglutamine Expanded ATXN7

Key Modulators of the Stress Granule Response TIA1, TDP-43, and G3BP1 are Altered by Polyglutamine Expanded ATXN7

The Integral Role of RNA in Stress Granule Formation and Function

Huntington disease: Advances in the understanding of its mechanisms

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