Interaction of the C9orf72-Amyotrophic Lateral Sclerosis-Related Proline–Arginine Dipeptide Repeat Protein with the RNA-Binding Protein NOVA1 Causes Decreased Expression of UNC13A Due to Enhanced Inclusion of Cryptic Exons, Which Is Reversed by Betulin Treatment DOI Creative Commons
Ru‐Huei Fu, Hui‐Jye Chen, Syuan‐Yu Hong

et al.

Cells, Journal Year: 2023, Volume and Issue: 12(20), P. 2476 - 2476

Published: Oct. 18, 2023

C9orf72 mutations are the most common form of familial amyotrophic lateral sclerosis (C9-ALS). It causes production proline-arginine dipeptide repeat proteins (PR-DPRs) in motor neurons (MNs), leading to molecular pathology characteristic ALS. UNC13A is critical for maintaining synaptic function MNs. Most ALS patients have nuclear deletion splicing repressor TDP-43 MNs, which inclusion cryptic exon (CE) mRNA, resulting nonsense-mediated mRNA decay and reduced protein expression. Therefore, this study, we explored role PR-DPR CE mRNA. Our results showed that (PR50) induced decreased expression human neuronal cell lines. We also identified an interaction between RNA-binding NOVA1 PR50 by yeast two-hybrid screening. known be with found knockdown enhanced Furthermore, naturally occurring triterpene betulin can inhibit PR50, thus preventing reduction This study linked developed candidate therapeutic strategies C9-ALS using betulin.

Language: Английский

Homozygous ALS-linked mutations in TARDBP/TDP-43 lead to hypoactivity and synaptic abnormalities in human iPSC-derived motor neurons DOI Creative Commons
Sarah Lépine,

Angela Nauleau-Javaudin,

Éric Deneault

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(3), P. 109166 - 109166

Published: Feb. 9, 2024

Cytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43 is a pathological hallmark motor neuron (MN) disease amyotrophic lateral sclerosis (ALS). Furthermore, while mutations in

Language: Английский

Citations

9
Research progress of PROTACs for neurodegenerative diseases therapy DOI

Zhifang Cai,

Zunhua Yang,

Huilan Li

et al.

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 147, P. 107386 - 107386

Published: April 18, 2024

Language: Английский

Citations

8
Synaptic Dysfunction and Plasticity in Amyotrophic Lateral Sclerosis DOI Open Access
Rosario Gulino

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(5), P. 4613 - 4613

Published: Feb. 27, 2023

Recent evidence has supported the hypothesis that amyotrophic lateral sclerosis (ALS) is a multi-step disease, as onset of symptoms occurs after sequential exposure to defined number risk factors. Despite lack precise identification these disease determinants, it known genetic mutations may contribute one or more steps leading ALS onset, remaining being linked environmental factors and lifestyle. It also appears evident compensatory plastic changes taking place at all levels nervous system during etiopathogenesis likely counteract functional effects neurodegeneration affect timing progression. Functional structural events synaptic plasticity probably represent main mechanisms underlying this adaptive capability, causing significant, although partial transient, resiliency affected by neurodegenerative disease. On other hand, failure functions be part pathological process. The aim review was summarize what today about controversial involvement synapses in etiopathogenesis, an analysis literature, not exhaustive, confirmed dysfunction early pathogenetic process ALS. Moreover, adequate modulation support function sparing delay

Language: Английский

Citations

21
Mitochondrial DNA Leakage and cGas/STING Pathway in Microglia: Crosstalk Between Neuroinflammation and Neurodegeneration DOI
Yuqian Liu,

Bohan Zhang,

Ruonan Duan

et al.

Neuroscience, Journal Year: 2024, Volume and Issue: 548, P. 1 - 8

Published: April 27, 2024

Language: Английский

Citations

7
Application of spatial transcriptome technologies to neurological diseases DOI Creative Commons

Dongshan Ya,

Yingmei Zhang, Qi Cui

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: March 3, 2023

Spatial transcriptome technology acquires gene expression profiles while retaining spatial location information, it displays the properties of cells in situ . Through investigation cell heterogeneity, microenvironment, function, and cellular interactions, can deeply explore pathogenic mechanisms cell-type-specific responses localization neurological diseases. The present article overviews technologies based on microdissection, hybridization, sequencing, capture, live labeling. Each is described along with its methods, detection throughput, resolution, benefits, drawbacks. Furthermore, their applications neurodegenerative disease, neuropsychiatric illness, stroke epilepsy are outlined. This information be used to understand disease mechanisms, pick therapeutic targets, establish biomarkers.

Language: Английский

Citations

11
Activating autophagy to eliminate toxic protein aggregates with small molecules in neurodegenerative diseases DOI

Yuqi Fu,

Jin Zhang, Rui Qin

et al.

Pharmacological Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 100053 - 100053

Published: March 1, 2025

Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson Huntington amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due intricate pathogenesis substantial variability among patients, including differences in environmental exposures genetic predispositions. One of the defining characteristics NDs is widely reported be buildup misfolded proteins. For example, disease marked by amyloid beta hyperphosphorylated Tau aggregates, whereas exhibits α-synuclein aggregates. Amyotrophic sclerosis dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, fused-in sarcoma involves mutant huntingtin polyglutamine These proteins key biomarkers also serve potential therapeutic targets, they can addressed through autophagy, a process that removes excess cellular inclusions maintain homeostasis. Various forms macroautophagy, chaperone-mediated microautophagy, hold promise eliminating toxic implicated NDs. In this review, we focus on elucidating regulatory connections between autophagy NDs, summarizing cause exploring impact mechanisms, discussing how regulate aggregation. Moreover, underscore activation strategy across different small molecules capable activating pathways, rapamycin targeting mTOR pathway clear Sertraline AMPK/mTOR/RPS6KB1 Tau, further illustrate NDs' intervention. Together, these findings would provide new insights into current research trends propose small-molecule drugs promising strategies future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview eliminate aggregates neurodegenerative diseases. It elucidates fascinating interrelationships "chasing escaping" phenomenon. discusses progress utilizing activate improve efficacy therapies removing

Language: Английский

Citations

0
Targeting TDP-43 Proteinopathy in hiPSC-Derived Mutated hNPCs with Mitoxantrone Drugs and miRNAs DOI Creative Commons
Uzair Ahmad Ansari, Ankita Srivastava, Ankur Kumar Srivastava

et al.

Pharmaceutics, Journal Year: 2025, Volume and Issue: 17(4), P. 410 - 410

Published: March 25, 2025

Background/Objectives: TDP-43 mutation-driven Amyotrophic Lateral Sclerosis (ALS) motor neuron disease is one of the most prominent forms (approximately 97%) in cases sporadic ALS. Dysfunctional autophagy and lysosomal function are prime mechanisms behind Mitoxantrone (Mito), a synthetic doxorubicin analog, an inhibitor DNA RNA synthesis/repair via intercalating with nitrogenous bases inhibiting topoisomerase II. The therapeutic potential miRNAs associated conditions has also been reported. This study explores Mito along against mutated protein-induced proteinopathy human-induced pluripotent stem cell (hiPSC)-derived human neural progenitor cells (hNPCs). Methods: HiPSCs for were differentiated into hNPCs used to explore at concentration 1 μM 24 h (the identified non-cytotoxic dose). effects on miRNA expression various cellular parameters such as mitochondrial dynamics, autophagy, stress granules assessed using high-throughput Open Array technique, immunocytochemistry, flow cytometry, immunoblotting, bioenergetic assay. Results: Mutated protein accumulation causes granule formation (G3BP1), dysfunction, SOD1 accumulation, hyperactivated ER hNPCs. show dysregulation six (miR-543, miR-34a, miR-200c, miR-22, miR-29b, miR-29c) A significant restoration mutation-induced alterations could be witnessed upon exposure Mito. Conclusions: Our indicates that miR-543, miR-34a have antisense alone combination Mitoxantrone.

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
Exploring antioxidant strategies in the pathogenesis of ALS DOI Creative Commons
Víctor Pinilla-González,

Benjamin Montecinos-Barrientos,

Clemente Martin-Kommer

et al.

Open Life Sciences, Journal Year: 2024, Volume and Issue: 19(1)

Published: Jan. 1, 2024

Abstract The central nervous system is essential for maintaining homeostasis and controlling the body’s physiological functions. However, its biochemical characteristics make it highly vulnerable to oxidative damage, which a common factor in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). ALS leading cause of motor neuron disease, characterized by rapidly progressing incurable condition. often results death from respiratory failure within 3–5 years onset first symptoms, underscoring urgent need address this medical challenge. aim study present available data supporting role stress mechanisms underlying discuss potential antioxidant therapies currently development. These improve quality life expectancy patients affected devastating disease.

Language: Английский

Citations

3
Unraveling the Epigenetic Landscape: Insights into Parkinson’s Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis DOI Creative Commons

Pierpaolo Di Martino,

Valentina Marcozzi,

Sandra Bibbò

et al.

Brain Sciences, Journal Year: 2024, Volume and Issue: 14(6), P. 553 - 553

Published: May 29, 2024

Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral (ALS) are examples of neurodegenerative movement disorders (NMDs), which defined by a gradual loss motor function that is frequently accompanied cognitive decline. Although genetic abnormalities have long been acknowledged as significant factors, new research indicates epigenetic alterations crucial for the initiation development disease. This review delves into complex interactions exist between pathophysiology NMDs mechanisms such DNA methylation, histone modifications, non-coding RNAs. Here, we examine how these changes could affect protein aggregation, neuroinflammation, gene expression patterns, thereby influencing viability functionality neurons. Through clarification terrain underpinning disorders, this seeks to enhance comprehension underlying illness augment creation innovative therapeutic strategies.

Language: Английский

Citations

3