Dysregulation of synaptic transcripts underlies network abnormalities in ALS patient-derived motor neurons DOI

Anna M. Kollstrøm,

Nicholas Christiansen, Axel Sandvig

et al.

AJP Cell Physiology, Journal Year: 2024, Volume and Issue: 328(3), P. C1029 - C1044

Published: Dec. 27, 2024

Amyotrophic lateral sclerosis (ALS) is characterized by dysfunction and loss of upper lower motor neurons. Several studies have identified structural functional alterations in the neurons before manifestation symptoms, yet underlying cause such how they contribute to progressive degeneration affected neuron networks remain unclear. Importantly, short- long-term spatiotemporal dynamics neuronal network activity make it challenging discern ALS-related reconfigurations emerge evolve. To address this, we systematically monitored with a confirmed endogenous C9orf72 mutation. We show that ALS patient-derived display time-dependent neural dysfunction, specifically reduced firing rate spike amplitude, impaired bursting, but higher overall synchrony activity. These changes coincided altered neurite outgrowth branching within networks. Moreover, transcriptional analyses revealed dysregulation molecular pathways involved synaptic development maintenance, outgrowth, cell adhesion, suggesting stabilization. This study identifies early as contributing mechanism resulting network-wide compensation, which may over time render vulnerable neurodegeneration.NEW & NOTEWORTHY RNA-sequencing expression genes plasticity. were accompanied impairments disrupted activity, compensations vulnerability ALS.

Language: Английский

Recent Therapeutic Gene Editing Applications to Genetic Disorders DOI Creative Commons
Éric Deneault

Current Issues in Molecular Biology, Journal Year: 2024, Volume and Issue: 46(5), P. 4147 - 4185

Published: April 30, 2024

Recent years have witnessed unprecedented progress in therapeutic gene editing, revolutionizing the approach to treating genetic disorders. In this comprehensive review, we discuss progression of milestones leading emergence clustered regularly interspaced short palindromic repeats (CRISPR)-based technology as a powerful tool for precise and targeted modifications human genome. CRISPR-Cas9 nuclease, base prime editing taken center stage, demonstrating remarkable precision efficacy ex vivo genomic modifications. Enhanced delivery systems, including viral vectors nanoparticles, further improved efficiency safety advancing their clinical translatability. The exploration CRISPR-Cas systems beyond commonly used Cas9, such development Cas12 Cas13 variants, has expanded repertoire tools, enabling more intricate interventions. Outstandingly, represents significant leap forward, given its unparalleled versatility minimization off-target effects. These innovations paved way multitude previously incurable disorders, ranging from monogenic diseases complex polygenic conditions. This review highlights latest innovative studies field, emphasizing breakthrough technologies preclinical trials, applications realm medicine. However, challenges effects ethical considerations remain, necessitating continued research refine profiles frameworks.

Language: Английский

Citations

8
Emerging perspectives of synaptic biomarkers in ALS and FTD DOI Creative Commons

Karrthik Krishnamurthy,

Raj Kumar Pradhan

Frontiers in Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 16

Published: Jan. 5, 2024

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are debilitating neurodegenerative diseases with shared pathological features like transactive response DNA-binding protein of 43 kDa (TDP-43) inclusions genetic mutations. Both involve synaptic dysfunction, contributing to their clinical features. Synaptic biomarkers, representing proteins associated function or structure, offer insights into disease mechanisms, progression, treatment responses. These biomarkers can detect early, track its evaluate therapeutic efficacy. ALS is characterized by elevated neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) blood, correlating progression. TDP-43 another key biomarker, mislocalization linked dysfunction. In FTD, tau studied as biomarkers. neuronal pentraxins (NPs), including pentraxin 2 (NPTX2), receptor (NPTXR), FTD pathology cognitive decline. Advanced technologies, machine learning (ML) artificial intelligence (AI), aid biomarker discovery drug development. Challenges this research include technological limitations detection, variability across patients, translating findings from animal models. ML/AI accelerate analyzing complex data predicting outcomes. early personalized strategies, mechanisms. While challenges persist, advancements interdisciplinary efforts promise revolutionize the understanding management FTD. This review will explore present comprehension discuss significance emphasize prospects obstacles.

Language: Английский

Citations

6
Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOs DOI Creative Commons
Matthew J. Keuss,

Peter Harly,

Eugeni Ryadnov

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 24, 2024

TDP-43 loss of function induces multiple splicing changes, including a cryptic exon in the amyotrophic lateral sclerosis and fronto-temporal lobar degeneration risk gene UNC13A, leading to nonsense-mediated decay UNC13A transcripts protein. is an active zone protein with integral role coordinating pre-synaptic function. Here, we show depletion severe reduction synaptic transmission, asynchronous pattern network activity. We demonstrate that these deficits are largely driven by single UNC13A. Antisense oligonucleotides targeting robustly rescue levels restore normal function, providing potential new therapeutic approach for ALS other TDP-43-related disorders.

Language: Английский

Citations

6
The Regulation of TDP-43 Structure and Phase Transitions: A Review DOI

Yanqing Liu,

Jiani Xiang,

Hang Gong

et al.

The Protein Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 22, 2025

Language: Английский

Citations

0
TDP43 is a newly identified substrate for PS1, enhancing the expression of APP following cleavage DOI Creative Commons

Hanlan Yin,

Yuxiang Wang,

Zhichao Ren

et al.

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: Feb. 23, 2025

Language: Английский

Citations

0
Dysregulation of synaptic transcripts underlies network abnormalities in ALS patient-derived motor neurons DOI Creative Commons

Anna M. Kollstrøm,

Nicholas Christiansen, Axel Sandvig

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 31, 2024

Amyotrophic lateral sclerosis (ALS) is characterized by dysfunction and loss of upper lower motor neurons. Several studies have identified structural functional alterations in the neurons before manifestation symptoms, yet underlying cause such how they contribute to progressive degeneration affected neuron networks remain unclear. Importantly, short long-term spatiotemporal dynamics neuronal network activity make it challenging discern ALS-related reconfigurations emerge evolve. To address this, we systematically monitored with a confirmed endogenous C9orf72 mutation. We show that ALS patient-derived display time-dependent neural dysfunction, specifically reduced firing rate spike amplitude, impaired bursting, but higher overall synchrony activity. These changes coincided altered neurite outgrowth branching within networks. Moreover, transcriptional analyses revealed dysregulation molecular pathways involved synaptic development maintenance, cell adhesion, suggesting stabilization. This study identifies early as contributing mechanism resulting network-wide compensation, which may over time render vulnerable neurodegeneration.

Language: Английский

Citations

1
The Current Potential Pathogenesis of Amyotrophic Lateral Sclerosis DOI
Shishi Jiang, Renshi Xu

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: unknown

Published: June 3, 2024

Language: Английский

Citations

0
Transcriptome-based screening in TARDBP/TDP-43 knock-in motor neurons identifies the NEDD8-activating enzyme inhibitor MLN4924 DOI Creative Commons
Sarah Lépine, Gilles Maussion,

Alexandria Schneider

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Abstract A growing body of knowledge implicates perturbed RNA homeostasis in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that currently has no cure and few available treatments. Dysregulation the multifunctional RNA-binding protein TDP-43 is increasingly regarded as convergent feature this disease, evidenced at neuropathological level by detection pathology most patient tissues, genetic identification disease-associated mutations its coding gene TARDBP. To characterize transcriptional landscape induced TARDBP mutations, we performed whole-transcriptome profiling motor neurons differentiated from two knock-in iPSC lines expressing ALS-linked variants p.A382T or p.G348C. Our results show significantly altered expression profiles mRNAs microRNAs 14q32 cluster MNs. Using mutation-induced signatures Connectivity Map database, identified compounds predicted to restore toward wild-type levels. Among top-scoring selected for further investigation, NEDD8-activating enzyme inhibitor MLN4924 effectively improved cell viability neuronal activity, highlighting possible role post-translational modification via NEDDylation pathobiology ALS.

Language: Английский

Citations

0
Dysregulation of synaptic transcripts underlies network abnormalities in ALS patient-derived motor neurons DOI

Anna M. Kollstrøm,

Nicholas Christiansen, Axel Sandvig

et al.

AJP Cell Physiology, Journal Year: 2024, Volume and Issue: 328(3), P. C1029 - C1044

Published: Dec. 27, 2024

Amyotrophic lateral sclerosis (ALS) is characterized by dysfunction and loss of upper lower motor neurons. Several studies have identified structural functional alterations in the neurons before manifestation symptoms, yet underlying cause such how they contribute to progressive degeneration affected neuron networks remain unclear. Importantly, short- long-term spatiotemporal dynamics neuronal network activity make it challenging discern ALS-related reconfigurations emerge evolve. To address this, we systematically monitored with a confirmed endogenous C9orf72 mutation. We show that ALS patient-derived display time-dependent neural dysfunction, specifically reduced firing rate spike amplitude, impaired bursting, but higher overall synchrony activity. These changes coincided altered neurite outgrowth branching within networks. Moreover, transcriptional analyses revealed dysregulation molecular pathways involved synaptic development maintenance, outgrowth, cell adhesion, suggesting stabilization. This study identifies early as contributing mechanism resulting network-wide compensation, which may over time render vulnerable neurodegeneration.NEW & NOTEWORTHY RNA-sequencing expression genes plasticity. were accompanied impairments disrupted activity, compensations vulnerability ALS.

Language: Английский

Citations

0