Multiomics approach identifies SERPINB1 as candidate progression biomarker for Spinocerebellar Ataxia type 2 DOI
Luis E. Almaguer-Mederos,

Jana Key,

Nihat Şen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 20, 2025

Abstract Background Spinocerebellar ataxia type 2 (SCA2) is a polyglutamine disorder, and variants in its disease protein Ataxin-2 act as modifiers the progression of Amyotrophic Lateral Sclerosis. There are no reliable molecular biomarkers for SCA2. Objectives The aim this study was to define novel biomarker candidates Methods Using cerebellar cervicothoracic spinal cord RNA from Atxn2 -CAG100-KnockIn wildtype mice, multi-omics conducted, followed by validation mice humans. Global transcriptome studies were conducted using Clariom D microarray. Extracted proteins analyzed LC-MS/MS global proteomics, Immobilized Metal Affinity Chromatography phosphoproteomics. Validation assessed expression RT-qPCR, abundance quantitative immunoblots ELISA. Patients with SCA2 diagnosed following standard procedures, age at onset, SARA score, INAS count, duration used clinical severity markers. Results Venn diagram comparisons across all OMICS datasets indicated that only Serpinb1a -transcript, SERPINB1A-protein -phosphopeptides consistently downregulated terminal stage 14-month-old KnockIn mice. Expression cerebellum 10 weeks (pre-manifest), 6-month-old (early ataxic), (late ataxic stage) confirmed progressive decrease mRNA level. SERPINB1 plasma levels significantly lower patients, displayed significant association CAG repeat length expanded ATXN2 alleles also showing trend towards significance score. Conclusions identified promising specificity pathomechanisms.

Language: Английский

Lipidomics of Huntington’s Disease: A Comprehensive Review of Current Status and Future Directions DOI Creative Commons
Ali Yilmaz, Sümeyya Akyol,

Nadia Ashrafi

et al.

Metabolites, Journal Year: 2025, Volume and Issue: 15(1), P. 10 - 10

Published: Jan. 2, 2025

Huntington's disease (HD) is a multifaceted neurological disorder characterized by the progressive deterioration of motor, cognitive, and psychiatric functions. Despite limited understanding its pathogenesis, research has implicated abnormal trinucleotide cytosine-adenine-guanine CAG repeat expansion in huntingtin gene (HTT) as critical factor. The development innovative strategies imperative for early detection predictive biomarkers, enabling timely intervention mitigating irreversible cellular damage. Lipidomics, comprehensive analytical approach, emerged an indispensable tool systematically characterizing lipid profiles elucidating their role pathology. A MedLine search was performed to identify studies that use lipidomics characterization HD. Search terms included "Huntington disease"; "lipidomics"; "biomarker discovery"; "NMR"; "Mass spectrometry". This review highlights significance HD diagnosis treatment, exploring changes brain lipids Recent breakthroughs techniques, particularly mass spectrometry NMR spectroscopy, have revolutionized research, researchers gain deeper insights into complex lipidome brain. broad spectrum alterations vital precise diagnostic evaluation effective management. integration with artificial intelligence interdisciplinary collaboration holds promise addressing clinical variability

Language: Английский

Citations

1
Common alterations to astrocytes across neurodegenerative disorders DOI
Aksinya Derevyanko, Tao Tao, Nicola J. Allen

et al.

Current Opinion in Neurobiology, Journal Year: 2025, Volume and Issue: 90, P. 102970 - 102970

Published: Jan. 28, 2025

Language: Английский

Citations

0
Brain Glycogen—Its Metabolic Role in Neuronal Health and Neurological Disorders—An Extensive Narrative Review DOI Creative Commons
Ana Isabel Beltrán-Velasco

Metabolites, Journal Year: 2025, Volume and Issue: 15(2), P. 128 - 128

Published: Feb. 13, 2025

Background: Brain glycogen is imperative for neuronal health, as it supports energy demands and metabolic processes. This review examines the pathways involved in storage utilization central nervous system, emphasizing their role both physiology pathology. It explores how alterations metabolism contribute to neurological disorders, including neurodegenerative diseases, epilepsy, conditions while highlighting bidirectional interaction between neurons glia maintaining brain homeostasis. Methods: A comprehensive search of articles published 2015 2025 was conducted using following databases: ScienceDirect, Scopus, Wiley, Web Science, Medline, PubMed. The selection relevant studies based on focus its conditions, with that did not meet inclusion criteria being excluded. Results: processes are subject rigorous regulation by astrocyte-neuron interactions, thereby ensuring homeostasis availability. dysregulation mobilization has been implicated development synaptic dysfunction, excitotoxicity, neurodegeneration a variety disorders. For instance, aberrant accumulation diseases such Lafora disease associated severe neurodegeneration, impaired shown exacerbate deficits Alzheimer's epilepsy. Conclusions: Targeting represents promising approach therapeutic intervention However, translation these strategies human models remains challenging, particularly regard long-term safety specificity glycogen-targeted therapies.

Language: Английский

Citations

0
CellFIE: Integrating Pathway Discovery With Pooled Profiling of Perturbations Uncovers Pathways of Huntington's Disease, Including Genetic Modifiers of Neuronal Development and Morphology DOI Creative Commons

Byunguk Kang,

Michael Murphy, Christopher Ng

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Abstract Genomic screens and GWAS are powerful tools for identifying disease-modifying genes, but it is often challenging to understand the pathways by which these genes function. Here, we take an integrated approach that combines network analysis imaging-based pooled genetic perturbation study examine modifiers of Huntington’s disease (HD). The computational highlighted several in a subnetwork enriched neuronal development morphology. To test functional roles developed experimental pipeline allows CRISPRi KD 21 human iPSC-derived neurons followed optical genotypes, arborization, multiplexed pathway activity morphological fingerprint readout. This recovered known involved morphology confirmed unexpected links from between HD Our overcomes challenges measurement function health could be adapted other phenotypes neurological diseases.

Language: Английский

Citations

0
Multiomics approach identifies SERPINB1 as candidate progression biomarker for Spinocerebellar Ataxia type 2 DOI
Luis E. Almaguer-Mederos,

Jana Key,

Nihat Şen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 20, 2025

Abstract Background Spinocerebellar ataxia type 2 (SCA2) is a polyglutamine disorder, and variants in its disease protein Ataxin-2 act as modifiers the progression of Amyotrophic Lateral Sclerosis. There are no reliable molecular biomarkers for SCA2. Objectives The aim this study was to define novel biomarker candidates Methods Using cerebellar cervicothoracic spinal cord RNA from Atxn2 -CAG100-KnockIn wildtype mice, multi-omics conducted, followed by validation mice humans. Global transcriptome studies were conducted using Clariom D microarray. Extracted proteins analyzed LC-MS/MS global proteomics, Immobilized Metal Affinity Chromatography phosphoproteomics. Validation assessed expression RT-qPCR, abundance quantitative immunoblots ELISA. Patients with SCA2 diagnosed following standard procedures, age at onset, SARA score, INAS count, duration used clinical severity markers. Results Venn diagram comparisons across all OMICS datasets indicated that only Serpinb1a -transcript, SERPINB1A-protein -phosphopeptides consistently downregulated terminal stage 14-month-old KnockIn mice. Expression cerebellum 10 weeks (pre-manifest), 6-month-old (early ataxic), (late ataxic stage) confirmed progressive decrease mRNA level. SERPINB1 plasma levels significantly lower patients, displayed significant association CAG repeat length expanded ATXN2 alleles also showing trend towards significance score. Conclusions identified promising specificity pathomechanisms.

Language: Английский

Citations

0