ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice DOI Creative Commons
Kristen H. Schuster,

Annie J. Zalon,

Danielle M. DiFranco

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: July 19, 2022

ABSTRACT Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia. Currently, no preventative or disease-modifying treatments exist for this progressive neurodegenerative disorder, although efforts using gene silencing approaches are under clinical trial investigation. The disease caused by a CAG repeat expansion in mutant gene, ATXN3 , producing an enlarged polyglutamine tract protein. Similar to other paradigmatic diseases, studies evaluating pathogenic mechanism focus primarily on neuronal implications. Consequently, therapeutic interventions often overlook non-neuronal contributions disease. Our lab recently reported that oligodendrocytes display some of earliest and dysfunction SCA3 mice. Evidence disease-associated oligodendrocyte signatures has also been including Alzheimer’s disease, ALS, Parkinson’s Huntington’s Here, we assess effects anti- antisense oligonucleotide (ASO) treatment premanifest symptomatic We report severe, but modifiable, deficit maturation toxic gain-of-function early transcriptionally, biochemically, functionally rescued with ASO. results highlight promising use ASO therapy across diseases requires glial targeting addition affected populations.

Language: Английский

ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice DOI
Kristen H. Schuster,

Annie J. Zalon,

Danielle M. DiFranco

et al.

Molecular Therapy, Journal Year: 2024, Volume and Issue: 32(5), P. 1359 - 1372

Published: Feb. 29, 2024

Language: Английский

Citations

7
Polyglutamine disease proteins: Commonalities and differences in interaction profiles and pathological effects DOI Creative Commons

Megan Bonsor,

Orchid Ammar,

Sigrid Schnoegl

et al.

PROTEOMICS, Journal Year: 2024, Volume and Issue: 24(12-13)

Published: April 14, 2024

Abstract Currently, nine polyglutamine (polyQ) expansion diseases are known. They include spinocerebellar ataxias (SCA1, 2, 3, 6, 7, 17), spinal and bulbar muscular atrophy (SBMA), dentatorubral‐pallidoluysian (DRPLA), Huntington's disease (HD). At the root of these neurodegenerative trinucleotide repeat mutations in coding regions different genes, which lead to production proteins with elongated polyQ tracts. While causative differ structure molecular mass, expanded domains drive pathogenesis all diseases. PolyQ tracts mediate association leading formation protein complexes involved gene expression regulation, RNA processing, membrane trafficking, signal transduction. In this review, we discuss commonalities differences among focusing on their function as well pathological features respective We present insights from AlphaFold‐predicted structural models biological roles polyQ‐containing proteins. Lastly, explore reported protein–protein interaction networks highlight shared interactions potential relevance development.

Language: Английский

Citations

6
Types of RNA therapeutics DOI
Pouya Goleij, Mehregan Babamohamadi,

Aryan Rezaee

et al.

Progress in molecular biology and translational science, Journal Year: 2024, Volume and Issue: unknown, P. 41 - 63

Published: Jan. 1, 2024

Language: Английский

Citations

5
Hereditary Ataxias: From Bench to Clinic, Where Do We Stand? DOI Creative Commons
Federica Pilotto, Andrea Del Bondio, Hélène Puccio

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(4), P. 319 - 319

Published: Feb. 9, 2024

Cerebellar ataxias are a wide heterogeneous group of movement disorders. Within this broad umbrella diseases, there both genetics and sporadic forms. The clinical presentation these conditions can exhibit diverse range symptoms across different age groups, spanning from pure cerebellar manifestations to sensory ataxia multisystemic diseases. Over the last few decades, advancements in our understanding molecular pathophysiology related dominant recessive have propelled field forward, paving way for innovative therapeutic strategies aimed at preventing arresting progression Nevertheless, rarity certain forms continues pose challenges, leading limited insights into etiology disease identification target pathways. Additionally, lack suitable models hampers efforts comprehensively understand foundations disease’s test novel interventions. In following review, we describe epidemiology, symptomatology, pathological hereditary ataxia, including prevalent less common Furthermore, illustrate pathways approaches currently undergoing investigation pre-clinical studies trials. Finally, address existing anticipated challenges within field, encompassing basic research endeavors.

Language: Английский

Citations

4
Spinocerebellar Ataxia Type 3 Pathophysiology—Implications for Translational Research and Clinical Studies DOI Open Access

Fabian Stahl,

Bernd O. Evert, Xinyu Han

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 3984 - 3984

Published: April 3, 2024

The spinocerebellar ataxias (SCA) comprise a group of inherited neurodegenerative diseases. Machado-Joseph Disease (MJD) or ataxia 3 (SCA3) is the most common autosomal dominant form, caused by expansion CAG repeats within ataxin-3 (ATXN3) gene. This mutation results in expression an abnormal protein containing long polyglutamine (polyQ) stretches that confers toxic gain function and leads to misfolding aggregation ATXN3 neurons. As result process, SCA3 patients are severely disabled die prematurely. Several screening approaches, e.g., druggable genome-wide drug library screenings have been performed, focussing on reduction stably overexpressed ATXN3(polyQ) improvement resultant toxicity. Transgenic overexpression models ATXN3, however, missed potential modulators endogenous regulation. In another approach identify modifiers using CRISPR/Cas9-modified SK-N-SH wild-type cell line with GFP-T2A-luciferase (LUC) cassette under control promotor, four statins were identified as activators expression. We here provide overview high throughput approaches yet performed find compounds genomic toxicity different model organisms lines ameliorate halt progression patients. Furthermore, putative role cholesterol diseases (NDDs) general particular discussed.

Language: Английский

Citations

4
Genome editing in spinocerebellar ataxia type 3 cells improves Golgi apparatus structure DOI Creative Commons
Yanlin Wang, Ying Cheng, Huifang Sun

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 9, 2025

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disease caused by repeat expansion of the CAG trinucleotide within exon 10 ATXN3 gene. This mutation results in production abnormal ataxin-3 protein containing extended polyglutamine tract, referred to as mutant ataxin-3. In this study, we investigated therapeutic potential CRISPR/Cas9-mediated genome editing for SCA3. First, designed a specific single-guide RNA targeting gene and constructed corresponding vector. Induced pluripotent stem cells (iPSCs) derived from SCA3 patient were then electroporated with CRISPR/Cas9 components. Positive clones screened validated PCR Sanger sequencing obtain genome-editing iPSCs (GE-iPSCs). Subsequently, pluripotency GE-iPSCs was confirmed, effects on expression Golgi apparatus morphology assessed using Western blotting immunofluorescence analyses. Our demonstrated that targeted insertion polyadenylation signals (PAS) upstream repeats effectively suppressed intervention also reduced formation neuronal nuclear inclusions differentiated neurons, restored structural integrity (which exhibited loose enlarged cells), increased levels proteins (GM130 GORASP2). conclusion, our findings indicate PAS represents promising strategy through editing.

Language: Английский

Citations

0
Emerging therapies in hereditary ataxias DOI

Mallory L S Eisel,

Matthew K. Burns, Tetsuo Ashizawa

et al.

Trends in Molecular Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 1, 2024

Language: Английский

Citations

2
Blood levels of neurofilament light are associated with disease progression in a mouse model of spinocerebellar ataxia type 3 DOI Creative Commons
David Mengel, Isabel G. Wellik, Kristen H. Schuster

et al.

Disease Models & Mechanisms, Journal Year: 2023, Volume and Issue: 16(9)

Published: Sept. 1, 2023

ABSTRACT Increased neurofilament light (NfL; NEFL) protein in biofluids is reflective of neurodegeneration and has gained interest as a biomarker across neurodegenerative diseases. In spinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited ataxia, patients exhibit progressive NfL increases peripheral blood when becoming symptomatic, remains stably elevated throughout further disease course. However, changes are not yet validated relevant preclinical SCA3 animal models, hindering its application during therapeutic development. We used ultra-sensitive single-molecule array (Simoa) to measure over progression YACQ84 mice, model SCA3, assessing relationships with measures severity including age, CAG repeat size magnetic resonance spectroscopy. mice exhibited plasma that were concomitant ataxia-related motor deficits well increased serum NfL, which correlated previously established neurometabolite abnormalities, two SCA3. Our findings establish mouse, supporting utility informing on coinciding timelines different pathogenesis.

Language: Английский

Citations

4
Regional sex differences in neurochemical profiles of healthy mice measured by magnetic resonance spectroscopy at 9.4 tesla DOI Creative Commons
Ivan Tkáč, Tiankai Xie,

Nitya Shah

et al.

Frontiers in Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: Oct. 25, 2023

Objective To determine sex differences in the neurochemical concentrations measured by vivo proton magnetic resonance spectroscopy ( 1 H MRS) of healthy mice on a genetic background commonly used for neurodegenerative disease models. Methods MRS data collected from wild type with C57BL/6 or related backgrounds seven prior studies were this retrospective analysis. be included, had to at 9.4 tesla field using advanced protocols, isoflurane anesthesia and similar animal handling number datasets male female available brain regions analyzed. Overall, 155 spectra 166 (321 total), six (brainstem, cerebellum, cortex, hippocampus, hypothalamus, striatum) various ages included. Results Concentrations taurine, total creatine (creatine + phosphocreatine), ascorbate, glucose glutamate consistently higher vs. most regions. Striatum was an exception mice. The difference pattern hypothalamus notably different other Interaction between age significant taurine cerebellum hippocampus. Conclusion Sex regional levels are small but age-dependent, consistent male–female across neuroendocrine region displays levels. Differences energy metabolism cellular density may underlie differences, metabolic rates females osmoregulatory antioxidant capacity males.

Language: Английский

Citations

4
Gene editing as a therapeutic strategy for spinocerebellar ataxia type-3 DOI Creative Commons
Nicole Déglon

Revue Neurologique, Journal Year: 2024, Volume and Issue: 180(5), P. 378 - 382

Published: April 4, 2024

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is a neurodegenerative disease caused by expanded polyglutamine repeats in exon 10 of the ataxin-3 gene, ATXN3. The accumulation mutant ATXN3 protein leads to severe clinical manifestations and premature death. Clinically, SCA3 pathology characterized progressive leading motor incoordination that may affect balance, gait speech, neuropathologically degeneration spinal cord cerebellum, well cerebral cortex basal ganglia. Although rare it most common autosomal dominant spinocerebellar worldwide. Its geographical distribution varies worldwide, with peak prevalence certain regions Brazil, Portugal China. In 1994, identification expansion gene made possible not only diagnose this but dissect mechanisms cellular degeneration. As monogenic for which symptomatic treatment available, represents an attractive therapeutic target editing strategies.

Language: Английский

Citations

1