Divergent Molecular Pathways for Toxicity of Selected Mutant C9ORF72-derived Dipeptide Repeats DOI Open Access

Sonia Okekenwa,

Ming Ying Tsai,

Patrick M. Dooley

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 29, 2023

Expansion of a hexanucleotide repeat in noncoding region the C9ORF72 gene is responsible for significant fraction Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) cases, but mechanisms linking mutant products to neuronal toxicity remain debatable. Pathogenesis was proposed involve production toxic RNA species and/or accumulation dipeptide repeats (DPRs) distinguishing between these has been challenging. In this study, we first use complementary model systems analyzing pathogenesis adult-onset neurodegenerative diseases characterize pathogenicity DPRs produced by Repeat Associated Non-ATG translation specific cellular compartments: isolated axoplasm giant synapse from squid. Results showed selective axonal presynaptic GP-DPRs, independent associated RNA. These effects involved MAPK signaling pathway that affects fast transport synaptic function, pathogenic mechanism shared with other proteins familial ALS, like SOD1 FUS. primary cultured neurons, GP not promote "dying-back" axonopathy seen ALS. Interestingly, GR- PR-DPRs, which had no effect on or transmission, were found disrupt nuclear membrane, promoting "dying-forward" neuropathy. All C9-DPR-mediated observed studies are whether corresponding mRNAs contained alternative codons. Finally, human tissues confirmed close association active P38 degenerating motor neurons as well GR-associated damage cortex. Collectively, our establish compartment-specific C9-DPRs degeneration, suggesting two may contribute disease heterogeneity synergize progression patients ALS FTD symptoms.

Language: Английский

Amyotrophic lateral sclerosis caused by hexanucleotide repeat expansions in C9orf72: from genetics to therapeutics DOI
Sarah Mizielinska, Guillaume M. Hautbergue, Tania F. Gendron

et al.

The Lancet Neurology, Journal Year: 2025, Volume and Issue: 24(3), P. 261 - 274

Published: Feb. 19, 2025

Language: Английский

Citations

3
Altered nuclear envelope homeostasis is a key pathogenic event in C9ORF72-linked ALS/FTD DOI Open Access
Riccardo Sirtori,

Michelle Gregoire,

Alicia Collins

et al.

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

Published: Feb. 4, 2024

SUMMARY ALS and FTD are complex neurodegenerative disorders that primarily affects motor neurons in the brain spinal cord, cortical frontal lobe. Although pathogenesis of ALS/FTD is unclear, recent research spotlights nucleocytoplasmic transport impairment, DNA damage, nuclear abnormalities as drivers neuronal death. In this study, we show loss envelope (NE) integrity a key pathology associated with pore (NPC) injury C9ORF72 mutant neurons. Importantly, mechanical stresses generated by cytoskeletal forces on NE can lead to NPC injury, integrity, accumulation damage. demonstrate restoring tensional homeostasis, disconnecting nucleus from cytoskeleton, rescue reduce damage cells. Together, our data suggest modulation homeostasis repair may represent novel promising therapeutic target for ALS/FTD.

Language: Английский

Citations

6
Synaptopathy: presynaptic convergence in frontotemporal dementia and amyotrophic lateral sclerosis DOI Creative Commons
Emma L. Clayton, Laura Huggon, Michael A. Cousin

et al.

Brain, Journal Year: 2024, Volume and Issue: 147(7), P. 2289 - 2307

Published: March 6, 2024

Abstract Frontotemporal dementia and amyotrophic lateral sclerosis are common forms of neurodegenerative disease that share overlapping genetics pathologies. Crucially, no significantly disease-modifying treatments available for either disease. Identifying the earliest changes initiate neuronal dysfunction is important designing effective intervention therapeutics. The genes mutated in genetic frontotemporal have diverse cellular functions, multiple mechanisms been proposed both. Identification a convergent mechanism would focus research targetable pathway, which could potentially effectively treat all (both familial sporadic). Synaptopathies diseases resulting from physiological synapses, define stages diseases, with synapse loss key feature dementia. At presynapse, process synaptic vesicle recruitment, fusion recycling necessary activity-dependent neurotransmitter release. unique distal location presynaptic terminal means tight spatio-temporal control homeostasis dependent on efficient local protein translation degradation. Recently, numerous publications shown mutations associated present synaptopathy characterized by dysfunction. This review will describe complex signalling membrane trafficking events occur at presynapse to facilitate neurotransmission summarize recent linking dementia/amyotrophic function. evidence indicates an early event illustrates need further this area, identify potential therapeutic targets ability impact pathomechanism.

Language: Английский

Citations

6
Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases DOI Creative Commons
Siwei Chu,

Xinyi Xie,

Carla Payan

et al.

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: Aug. 7, 2023

Abstract The AAA + ATPase valosin containing protein (VCP) is essential for cell and organ homeostasis, especially in cells of the nervous system. As part a large network, VCP collaborates with many cofactors to ensure proteostasis under normal, stress, disease conditions. A number mutations have revealed importance human health. In particular, facilitates dismantling aggregates removal dysfunctional organelles. These are critical events prevent malfunction brain other parts line this idea, mutants linked onset progression neurodegeneration diseases. intricate molecular mechanisms that connect distinct pathologies continue be uncovered. Emerging evidence supports model controls cellular functions on multiple levels type specific fashion. Accordingly, derail homeostasis through several can instigate disease. Our review focuses association between neurodegeneration. We discuss latest insights field, emphasize open questions, speculate potential as drug target some most devastating forms

Language: Английский

Citations

15
New Insights into Molecular Mechanisms Underlying Neurodegenerative Disorders DOI Creative Commons
Jiale Liu, Wenjie Duan,

Yushu Deng

et al.

Journal of Integrative Neuroscience, Journal Year: 2023, Volume and Issue: 22(3)

Published: May 6, 2023

As a large and heterogeneous group of disorders, neurodegenerative diseases are characterized by the progressive loss structure or function in neurons, finally leading to neuronal death. Neurodegenerative cause serious threat patient’s quality life most common Alzheimer’s disease Parkinson’s disease. Currently, little is known detailed etiology these disorders; as such, there no effective treatments available. Furthermore, lack targeted, effective, resolvable therapy for diseases, represents an expanding research field discovery new therapeutic strategies. Investigations potential pathogenesis will become basis preventing occurrence development finding therapies. Existing theories mechanisms, such genetic environmental factors, abnormal protein accumulation, oxidative stress, intricately associated with each other. However, molecular theory that can entirely explain pathological processes underlying diseases. Due experimental technology support multidisciplinary integration, it has been possible perform more in-depth on targets have many exciting discoveries terms original mechanisms. With this review, we intend review existing literature provide insights into mechanisms

Language: Английский

Citations

14
Current insights in the molecular genetic pathogenesis of amyotrophic lateral sclerosis DOI Creative Commons

Zhou Wan,

Renshi Xu

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

Published: Aug. 10, 2023

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that leads to the massive loss of motor neurons in cerebrum, brain stem spinal cord. It affects not only but also other glial cells, resulting muscle atrophy, severe disability eventual death due respiratory failure. The pathogenesis ALS fully understood. Currently, several factors are considered be involved ALS, such as genetic factors, imbalances protein homeostasis, RNA metabolism disorders, mitochondrial dysfunctions, glutamate-mediated excitatory toxicities intra-neuronal material transport disorders neurons. study mutations related will link molecular cellular mechanisms disease, thus enhancing understanding its occurrence progression, thereby providing new insights for ALS. This review summarizes current

Language: Английский

Citations

11
A review on oxidative stress in organophosphate-induced neurotoxicity DOI
Dietrich E. Lorke, Murat Öz

The International Journal of Biochemistry & Cell Biology, Journal Year: 2025, Volume and Issue: unknown, P. 106735 - 106735

Published: Jan. 1, 2025

Language: Английский

Citations

0
A molecular systems architecture of neuromuscular junction in amyotrophic lateral sclerosis DOI Creative Commons

V. A. Shiva Ayyadurai,

Prabhakar Deonikar,

Roger D. Kamm

et al.

npj Systems Biology and Applications, Journal Year: 2025, Volume and Issue: 11(1)

Published: March 17, 2025

A molecular systems architecture is presented for the neuromuscular junction (NMJ) in order to provide a framework organizing complexity of biomolecular interactions amyotrophic lateral sclerosis (ALS) using systematic literature review process. ALS fatal motor neuron disease characterized by progressive degeneration upper and lower neurons that supply voluntary muscles. The contains cells such as neurons, skeletal muscle cells, astrocytes, microglia, Schwann endothelial which are implicated pathogenesis ALS. This provides multi-layered understanding intra- inter-cellular microenvironment, may be utilized target identification, discovery single combination therapeutics, clinical strategies treat

Language: Английский

Citations

0
Amyotrophic Lateral Sclerosis: Focus on Cytoplasmic Trafficking and Proteostasis DOI Creative Commons

Shrilaxmi Ms,

Saradindu Banerjee, Santosh R. D’Mello

et al.

Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown

Published: April 3, 2025

Abstract Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease characterized by the pathological loss of upper lower neurons. Whereas most ALS cases are caused combination environmental factors genetic susceptibility, in relatively small proportion cases, disorder results from mutations genes that inherited. Defects several different cellular mechanisms processes contribute to selective neurons (MNs) ALS. Prominent among these accumulation aggregates misfolded proteins or peptides which toxic These accumulating stress ability endoplasmic reticulum (ER) function normally, cause defects transport between ER Golgi, impair RNA, proteins, organelles, such as mitochondria, within axons dendrites, all degeneration MNs. Although dysfunction variety combines towards pathogenesis ALS, this review, we focus on recent advances concerning involvement defective stress, vesicular axonal transport. Graphical

Language: Английский

Citations

0
Axon guidance genes modulate neurotoxicity of ALS-associated UBQLN2 DOI Creative Commons
Sang Hwa Kim,

Kye D Nichols,

Eric N. Anderson

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: April 11, 2023

Mutations in the ubiquitin (Ub) chaperone Ubiquilin 2 (UBQLN2 ) cause X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) through unknown mechanisms. Here, we show that aggregation-prone, ALS-associated mutants UBQLN2 ALS trigger heat stress-dependent neurodegeneration Drosophila . A genetic modifier screen implicated endolysosomal axon guidance genes, including netrin receptor, Unc-5, as key modulators toxicity. Reduced gene dosage Unc-5 or its coreceptor Dcc/frazzled diminished neurodegenerative phenotypes, motor dysfunction, neuromuscular junction defects, shortened lifespan, flies expressing alleles. Induced pluripotent stem cells (iPSCs) harboring knockin mutations exhibited lysosomal defects while inducible neurons (iMNs) alleles cytosolic inclusions, reduced neurite complexity, growth cone were partially reversed by silencing UNC5B DCC The combined findings suggest altered dynamics are a conserved pathomechanism UBQLN2-associated ALS/FTD.

Language: Английский

Citations

7