Complex Genetic Framework in Familial Amyotrophic Lateral Sclerosis With a C9ORF72 Mutation: A Case Report DOI Open Access
Andrey Frolov,

Elizabeth D'sa,

C. M. B. Henderson

et al.

Cureus, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 19, 2024

A significantly diverse clinical presentation of amyotrophic lateral sclerosis (ALS), even in its best-studied familial form, continues to hinder current efforts develop effective disease-modifying drugs for the cure this rapidly progressive, fatal neuromuscular disease. We have previously shown that heterogeneity sporadic ALS (sALS) could be explained, at least part, by polygenic nature as well presence mutated genes linked non-ALS neurological diseases and known mediate ALS-related pathologies. hypothesized a similar genetic framework also present patients with (fALS). To test hypothesis, we conducted post-mortem screening an individual fALS mutation C9ORF72 gene. mutations are highly penetrant majority patients. Genetic whole exome sequencing (WES) on next generation (NGS) Illumina platform (San Diego, CA, USA) followed examination respective rare (minor allele frequency (MAF) ≤ 0.01) pathological/deleterious variants yielded results consistent our hypothesis complex fALS. Additional members were identified when low-frequency (0.01 < MAF 0.05) analyzed biallelic AHNAK2, GLI3, PTIRM1, ZNF254 variants, warranting closer look their potentially important role modifiers link both disorders/ALS cancer. Therefore, addition using standard panel genes, supplementary WES very beneficial development personalized treatment search efficient drugs.

Language: Английский

Exploring epigenetic modifications as potential biomarkers and therapeutic targets in amyotrophic lateral sclerosis DOI
Xiaotong Hou,

JingSi Jiang,

Min Deng

et al.

Journal of Neurology, Journal Year: 2025, Volume and Issue: 272(4)

Published: April 1, 2025

Language: Английский

Citations

0
HR-MS Analysis of the Covalent Binding of Edaravone to 5-Formylpyrimidine Bases and a DNA Oligonucleotide Containing a 5-Formylcytidine Residue. DOI
Romain Regnault, Mostafa Kouach, Laurence Goossens

et al.

PubMed, Journal Year: 2025, Volume and Issue: 39(14), P. e10050 - e10050

Published: July 30, 2025

Edaravone (EDA) is a radical scavenger and an antioxidant drug approved to treat amyotrophic lateral sclerosis used as research tool explore treatment of neurodegenerative diseases cancers. It also reactive agent, known PMP (1-phenyl-3-methyl-5-pyrazolone), for the analysis polysaccharides composition. EDA can react with sugars aromatic aldehydes. In this context, we have investigated reactivity toward biologically relevant formylated nucleobases, nucleosides, oligonucleotide containing residue. The formation both mono- bis-adducts between nucleobases (5-formyluracil (5fU) 5-formylcytosine (5fC)) or corresponding nucleosides 5-fdU 5-fdC was characterized using high-resolution mass spectrometry (HR-MS). Similarly, covalent binding 8-mer palindromic d (TATG[*C]ATA) single residue [*C] under physiological conditions spectrometry. For first time, shown pyrimidines. Covalent stable adducts were identified. found efficiently generate bis-adducts. rate mono-adduct five times higher than that bis-adduct. reaction aldehydic DNA modifications such 5fU/5fC may important consequences in terms gene expression. These observations raise implications epigenetic contribution mechanism action EDA. biological our vitro results are discussed, notably frame

Language: Английский

Citations

0
An ALS assembly modulator signature in peripheral blood mononuclear cells: implications for ALS pathophysiology, therapeutics, and diagnostics DOI Creative Commons

Shao Feng Yu,

Maya Michon,

Anuradha F. Lingappa

et al.

Clinical Proteomics, Journal Year: 2025, Volume and Issue: 22(1)

Published: April 28, 2025

Abstract Assembly modulators are a new class of allosteric site-targeted therapeutic small molecules, some which effective at restoring nuclear localization TDP-43 in ALS cellular models, and display efficacy variety animal models. These compounds have been shown to bind selectively subset protein disulfide isomerase (PDI), implicated pathophysiology. The targeted PDI is found within novel, transient energy-dependent multi-protein complex that includes other important members the interactome, such as TDP-43, RanGTPase, selective autophagy receptor p62/SQSTM1. We demonstrate here similar drug target present PBMCs isolated by resin affinity chromatography (eDRAC) characterized mass spectrometry Western blot (WB). Signature alterations composition from patients compared healthy individuals were identified WB eDRAC bound proteins, thereby extending earlier literature suggesting PBMC dysfunction ALS. Changes include diminished p62/SQSTM1 appearance 17 kDa post-translationally modified form RanGTPase. changes not readily apparent analysis whole cell extracts, individual components comprise only percentages total those component proteins extract. Furthermore, blood shows distinctive degradation RanGTPase observed individuals. This appears be rescued treatment for 72 h with ALS-active assembly modulator molecules. Our findings consistent hypothesis fundamentally disorder homeostasis can detected early, prior disability, methods described, restored state treatment.

Language: Английский

Citations

0
Complex Genetic Framework in Familial Amyotrophic Lateral Sclerosis With a C9ORF72 Mutation: A Case Report DOI Open Access
Andrey Frolov,

Elizabeth D'sa,

C. M. B. Henderson

et al.

Cureus, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 19, 2024

A significantly diverse clinical presentation of amyotrophic lateral sclerosis (ALS), even in its best-studied familial form, continues to hinder current efforts develop effective disease-modifying drugs for the cure this rapidly progressive, fatal neuromuscular disease. We have previously shown that heterogeneity sporadic ALS (sALS) could be explained, at least part, by polygenic nature as well presence mutated genes linked non-ALS neurological diseases and known mediate ALS-related pathologies. hypothesized a similar genetic framework also present patients with (fALS). To test hypothesis, we conducted post-mortem screening an individual fALS mutation C9ORF72 gene. mutations are highly penetrant majority patients. Genetic whole exome sequencing (WES) on next generation (NGS) Illumina platform (San Diego, CA, USA) followed examination respective rare (minor allele frequency (MAF) ≤ 0.01) pathological/deleterious variants yielded results consistent our hypothesis complex fALS. Additional members were identified when low-frequency (0.01 < MAF 0.05) analyzed biallelic AHNAK2, GLI3, PTIRM1, ZNF254 variants, warranting closer look their potentially important role modifiers link both disorders/ALS cancer. Therefore, addition using standard panel genes, supplementary WES very beneficial development personalized treatment search efficient drugs.

Language: Английский

Citations

0