Oxidative stress and ion channels in neurodegenerative diseases

Frontiers in Physiology, Journal Year: 2024, Volume and Issue: 15

Published: Jan. 29, 2024

Numerous neurodegenerative diseases result from altered ion channel function and mutations. The intracellular redox status can significantly alter the gating characteristics of channels. Abundant associated with oxidative stress have been documented, including Parkinson’s, Alzheimer’s, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington’s disease. Reactive oxygen nitrogen species compounds trigger posttranslational alterations that target specific sites within subunits responsible for assembly. These include adjustment cysteine residues through reactions induced by reactive (ROS), nitration, S-nitrosylation assisted nitric oxide tyrosine peroxynitrite. Several channels directly investigated their functional responses to oxidizing agents stress. This review primarily explores relationship potential links between in conditions, such as cerebellar ataxias Parkinson’s correlation could hold promise developing innovative therapies common diseases.

Language: Английский

---

Molecular Biomarkers of Neurodegenerative Disorders: A Practical Guide to Their Appropriate Use and Interpretation in Clinical Practice

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(8), P. 4323 - 4323

Published: April 13, 2024

Neurodegenerative disorders (NDs) represent a group of different diseases characterized by the progressive degeneration and death nervous system's cells. The diagnosis is challenging, especially in early stages, due to no specific clinical signs symptoms. In this context, laboratory medicine could support clinicians detecting differentiating NDs. Indeed, biomarkers indicate pathological mechanisms underpinning ideal biofluid for NDs cerebrospinal fluid (CSF), which has limitations, hampering its widespread use practice. However, intensive efforts are underway introduce high-sensitivity analytical methods detect ND alternative nonivasive biofluid, such as blood or saliva. This study presents an overview molecular currently used For some diseases, Alzheimer's disease multiple sclerosis, well established recommended guidelines. most NDs, research ongoing identify reliable biomarkers, consensus yet been achieved.

Language: Английский

---

Longitudinal Changes in Patient‐ and Clinical‐Reported Outcomes in Early Spinocerebellar Ataxia Types 1, 2, 3, and 6 from the IDEA Study

Movement Disorders Clinical Practice, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Abstract Background Clinical outcomes assessments (COAs) in spinocerebellar ataxia (SCA) need to be standardized, ataxia‐specific, sensitive change, clinically relevant, and meaningful patients. Objectives To evaluate the longitudinal 1‐ 2‐year performances of different patient reported outcomes, including Patient Reported Outcome Measure Ataxia (PROM‐Ataxia), clinician FARS SARA, those with early manifest symptoms SCA 1, 2, 3, 6. Methods We studied 53 patients stage SCA1‐3 SCA6 from The Instrumented Data Exchange for Study 24 age‐matched healthy controls. Participants were seen every 6 months 2 years. Mixed models used estimate change over 12‐ 24‐months follow‐up. Changes on FARS‐FS PGI‐C as anchors changes. Results Among persons SCA, mean age was 48.7 years SARA score 9.3. Few measures showed statistically significant changes at 12 months. At 24‐months, FARS‐ADL, PROM‐Ataxia total, physical, ADL scores strongest associations change. Conclusions or derived outcome measures, such FARS‐ADL sub domain PROM‐Ataxia, can capture patients’ symptom experience a period its impact daily activities, even disease. More work is needed identify that reliably earlier.

Language: Английский

---

Real-life Wrist Movement Patterns Capture Motor Impairment in Individuals with Ataxia-Telangiectasia

The Cerebellum, Journal Year: 2022, Volume and Issue: 22(2), P. 261 - 271

Published: March 16, 2022

Language: Английский

---

Antisense Oligonucleotide Silencing Reverses Abnormal Neurochemistry in Spinocerebellar Ataxia 3 Mice

Annals of Neurology, Journal Year: 2023, Volume and Issue: 94(4), P. 658 - 671

Published: May 27, 2023

Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia, and biomarkers are needed to noninvasively monitor disease progression treatment response. Anti-ATXN3 antisense oligonucleotide (ASO) has been shown mitigate neuropathology rescue motor phenotypes in SCA3 mice. Here, we investigated whether repeated ASO administration reverses brainstem cerebellar neurochemical abnormalities by magnetic resonance spectroscopy (MRS).

Language: Английский

---

Hereditary Ataxias: From Bench to Clinic, Where Do We Stand?

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

---

Psychometric Validation of the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) in Patients With Spinocerebellar Ataxia

The Cerebellum, Journal Year: 2024, Volume and Issue: unknown

Published: June 12, 2024

This study aimed to generate evidence support psychometric validity of the modified functional Scale for Assessment and Rating Ataxia (f-SARA) among patients with spinocerebellar ataxia (SCA). Psychometric measurement properties minimal change thresholds f-SARA were evaluated using data from a cohort SCA subjects (recruited at Massachusetts General Hospital [MGH]; n = 33) phase 3 trial troriluzole in adults (NCT03701399 [Study 206]; 217), including subset SCA3 genotype (n 89). item ceiling effects absent within MGH cohort, while floor present. Excellent internal consistency reliability was demonstrated (α

Language: Английский

---

Measurement Properties of the Friedreich Ataxia Rating Scale in Patients with Spinocerebellar Ataxia

Neurology and Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

The Friedreich Ataxia Rating Scale–Activities of Daily Living (FARS-ADL) is a valid, highly utilized measure for assessing ADL impacts in patients with ataxia. We provide evidence the psychometric validity FARS-ADL two cohorts spinocerebellar ataxia (SCA). Using data from cohort real-world subjects SCA (recruited at Massachusetts General Hospital [MGH]; n = 33) and phase 3 trial troriluzole adults (NCT03701399 [Study 206]; 217), comprising subset SCA3 genotype (n 89), measurement properties minimal change thresholds were examined. Ceiling effects absent within MGH while floor observed eight nine items. Excellent internal consistency reliability was (αtotal 0.88; αitems−removed 0.86–0.87), item-to-total correlations acceptable (r 0.55–0.89 per item). Convergent divergent supported strong demonstrated between scales measuring similar concepts (Neuro-QOL [Upper], Neuro-QOL [Lower], PROM-ADL, PROM-PHYS, FARS-FUNC; all P < 0.001) weaker shown measures differing constructs. A two- to three-point threshold meaningful changes as 0.5 × SD 2.43, SEM 2.19. Mean baseline classified "improved," "no change," or "deteriorated" −0.54, 0.22, 1.47, respectively. Similar trends Study 206 all-SCA cohorts. Psychometric evaluation showed that performed well on analyses examining can detect SCA, including those SCA3. ClinicalTrials.gov identifier, NCT03701399 (Study 206).

Language: Английский

---

Gene Therapy for Polyglutamine Spinocerebellar Ataxias: Advances, Challenges, and Perspectives

Movement Disorders, Journal Year: 2021, Volume and Issue: 36(12), P. 2731 - 2744

Published: Oct. 10, 2021

ABSTRACT Polyglutamine spinocerebellar ataxias (SCAs) comprise a heterogeneous group of six autosomal dominant caused by cytosine–adenine–guanine repeat expansions in the coding region single genes. Currently, there is no curative or disease‐slowing treatment for these disorders, but their monogenic inheritance has informed rationales development gene therapy strategies. In fact, RNA interference strategies have shown promising findings cellular and/or animal models SCA1, SCA3, SCA6, and SCA7. addition, antisense oligonucleotide provided encouraging proofs concept SCA2, SCA7, they not yet progressed to clinical trials. On contrary, editing strategies, such as clustered regularly interspaced short palindromic (CRISPR/Cas9), been introduced limited extent disorders. this article, we review available literature about polyglutamine SCAs discuss main technological ethical challenges toward prospect use future Although therapies are further along path phases, recent failure three trials Huntington's disease may delay utilization SCAs, offer lessons that could optimize likelihood success potential studies. © 2021 International Parkinson Movement Disorder Society

Language: Английский

---

The Homogeneous Azorean Machado-Joseph Disease Cohort: Characterization and Contributions to Advances in Research

Biomedicines, Journal Year: 2023, Volume and Issue: 11(2), P. 247 - 247

Published: Jan. 18, 2023

Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant worldwide. MJD characterized by late-onset progressive cerebellar associated with variable clinical findings, including pyramidal signs and a dystonic-rigid extrapyramidal syndrome. In Portuguese archipelago of Azores, worldwide population cluster for this disorder (prevalence 39 in 100,000 inhabitants), cohort mutation carriers belonging to extensively studied pedigrees has been followed since late 1990s. Studies homogeneous Azorean have contributing crucial information natural history as well allowing identification novel molecular biomarkers. Moreover, interventional studies globally rare yet untreatable are emerging, should be even more important recruitment trial participants. paper, we profile carriers, constituted at baseline 20 pre-ataxic 52 patients, which currently integrates European spinocerebellar 3/Machado-Joseph Initiative (ESMI), large longitudinal cohort. summarize main based on highlight contributions made advances research. Knowledge not only context emergent trials but also pertinent implementation adequate measures, constituting relevant Lay Associations providing data guide healthcare decision makers.

Language: Английский

---