Twenty-five years since the identification of the first SCA gene: history, clinical features and perspectives for SCA1

Martins, Carlos Roberto; Borba, Fabrício Castro de; Martinez, Alberto Rolim Muro; Rezende, Thiago Junqueira Ribeiro de; Cendes, Iscia Teresinha Lopes; Pedroso, José Luiz; Barsottini, Orlando Graziani Póvoas; Júnior, Marcondes Cavalcante França

doi:10.1590/0004-282x20180080

Cited by 7 publications

(7 citation statements)

References 63 publications

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“…Cerebral involvement was detected with higher sensitivity by diffusion than structural MRI, consistent with microstructural changes preceding tissue loss. Prior work had shown damage to cerebral WM tracts, for example, CC and CST, in more advanced cohorts with SCA1 and SCA3 7,57 . The current study revealed the presence of these WM alterations earlier in the disease course.…”

Section: Discussionsupporting

confidence: 61%

Clinically Meaningful Magnetic Resonance Endpoints Sensitive to Preataxic Spinocerebellar Ataxia Types 1 and 3

Chandrasekaran

Petit

Park

et al. 2022

Annals of Neurology

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This study was undertaken to identify magnetic resonance (MR) metrics that are most sensitive to early changes in the brain in spinocerebellar ataxia type 1 (SCA1) and type 3 (SCA3) using an advanced multimodal MR imaging (MRI) protocol in the multisite trial setting. Methods: SCA1 or SCA3 mutation carriers and controls (n = 107) underwent MR scanning in the US-European READISCA study to obtain structural, diffusion MRI, and MR spectroscopy data using an advanced protocol at 3T. Morphometric, microstructural, and neurochemical metrics were analyzed blinded to diagnosis and compared between preataxic SCA (n = 11 SCA1, n = 28 SCA3), ataxic SCA (n = 14 SCA1, n = 37 SCA3), and control (n = 17) groups using nonparametric testing accounting for multiple comparisons. MR metrics that were most sensitive to preataxic abnormalities were identified using receiver operating characteristic (ROC) analyses.

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Section: Discussionsupporting

confidence: 61%

Clinically Meaningful Magnetic Resonance Endpoints Sensitive to Preataxic Spinocerebellar Ataxia Types 1 and 3

Chandrasekaran

Petit

Park

et al. 2022

Annals of Neurology

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“…SCA1, a rapidly progressive PolyQ disorder, is caused by a mutation in the gene encoding Atxn1, resulting in a PolyQ expansion in Atxn1 beyond a threshold (Martins Junior et al, ; Zoghbi & Orr, ). This extended PolyQ tract affects Atxn1 folding and renders it prone to aggregation in the nucleus.…”

Section: Resultsmentioning

confidence: 99%

“…Wild-type Atxn1 contains 6-44 PolyQ repeats in healthy humans, while the mutant Atxn1 contains an expanded PolyQ stretch containing up to 83 repeats of glutamine (Zoghbi & Orr, 2009). Such PolyQ expansions in Atxn1 lead to spinocerebellar ataxia type 1 (SCA1; Martins Junior et al, 2018). Similarly, an expansion of CAG repeats in the exon1 of the HTT gene, leads to Huntingtin disease (Harding & Tong, 2018).…”

Section: Introductionmentioning

confidence: 99%

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“Trim”ming PolyQ proteins with engineered PML

Dhar

Arsiwala

Murali

et al. 2019

Biotech & Bioengineering

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Protein abnormalities are the major cause of neurodegenerative diseases such as spinocerebellar ataxia (SCA). Protein misfolding and impaired degradation leads to the build‐up of protein aggregates inside the cell, which may further cause cellular degeneration. Reducing levels of either the soluble misfolded form of the protein or its precipitated aggregate, even marginally, could significantly improve cellular health. Despite numerous pre‐existing strategies to target these protein aggregates, there is considerable room to improve their specificity and efficiency. In this study, we demonstrated the enhanced intracellular degradation of both monomers and aggregates of mutant ataxin1 (Atxn1 82Q) by engineering an E3 ubiquitin ligase enzyme, promyelocytic leukemia protein (PML). Specifically, we showed enhanced degradation of both soluble and aggregated Atxn1 82Q in mammalian cells by targeting this protein using PML fused to single chain variable fragments (scFvs) specific for monomers and aggregates of the target protein. The ability to solubilize Atxn1 82Q aggregates was due to the PML‐mediated enhanced SUMOylation of the target protein. This ability to reduce the intracellular levels of both misfolded forms of Atxn1 82Q may not only be useful for treating SCA, but also applicable for the treatment of other PolyQ disorders.

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“…Q46), it was not unexpected that CHDI-180 also bound to aggregated ataxin 1 (see Supplementary Fig. S11 ), another polyQ- repeat protein that plays a significant pathophysiological role in Spinocerebellar ataxia (reviewed in 72 – 74 ). However, the ARG signals were much lower in brain sections of 2 Sca mouse models 75 , 76 when compared to the R6/2 HD model; the reason for the observed ARG signal differences between the Sca and HD models is not known, but may be attributed to differences in ataxin- vs. huntingtin-aggregate affinities and/or in mouse model aggregate load expression.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates

Herrmann

Heßmann

Schaertl

et al. 2021

Sci Rep

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Huntington’s disease (HD) is caused by a CAG trinucleotide repeat expansion in the first exon of the huntingtin (HTT) gene coding for the huntingtin (HTT) protein. The misfolding and consequential aggregation of CAG-expanded mutant HTT (mHTT) underpin HD pathology. Our interest in the life cycle of HTT led us to consider the development of high-affinity small-molecule binders of HTT oligomerized/amyloid-containing species that could serve as either cellular and in vivo imaging tools or potential therapeutic agents. We recently reported the development of PET tracers CHDI-180 and CHDI-626 as suitable for imaging mHTT aggregates, and here we present an in-depth pharmacological investigation of their binding characteristics. We have implemented an array of in vitro and ex vivo radiometric binding assays using recombinant HTT, brain homogenate-derived HTT aggregates, and brain sections from mouse HD models and humans post-mortem to investigate binding affinities and selectivity against other pathological proteins from indications such as Alzheimer’s disease and spinocerebellar ataxia 1. Radioligand binding assays and autoradiography studies using brain homogenates and tissue sections from HD mouse models showed that CHDI-180 and CHDI-626 specifically bind mHTT aggregates that accumulate with age and disease progression. Finally, we characterized CHDI-180 and CHDI-626 regarding their off-target selectivity and binding affinity to beta amyloid plaques in brain sections and homogenates from Alzheimer’s disease patients.

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Twenty-five years since the identification of the first SCA gene: history, clinical features and perspectives for SCA1

Cited by 7 publications

References 63 publications

Clinically Meaningful Magnetic Resonance Endpoints Sensitive to Preataxic Spinocerebellar Ataxia Types 1 and 3

Clinically Meaningful Magnetic Resonance Endpoints Sensitive to Preataxic Spinocerebellar Ataxia Types 1 and 3

“Trim”ming PolyQ proteins with engineered PML

Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates

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