HDAC6 inhibition as a mechanism to prevent axon degeneration in the mSOD1G93Amouse model of ALS DOI Open Access
Andrew J. Phipps,

Samuel Dwyer,

Jessica M. Collins

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Авг. 29, 2023

Abstract The loss of upper and lower motor neurons, their axons is central to the function death in amyotrophic lateral sclerosis (ALS). Due diverse range genetic environmental factors that contribute pathogenesis ALS, there have been difficulties developing effective therapies for ALS. One dichotomy emerging field protection neuronal cell soma itself does not prevent axonal vulnerability degeneration, suggesting need targeted therapeutics axon degeneration. Post-translational modifications protein acetylation can alter function, stability half-life individual proteins, be enzymatically modified by histone acetyltransferases (HATs) deacetyltransferases (HDACs), which add, or remove acetyl groups, respectively. Maintenance post-translational microtubule has suggested as a potential mechanism stabilise neurodegeneration This study utilized an orally dosed HDAC6 specific inhibitor, ACY-738, deacetylation stabilize microtubules mSOD1 G93A mouse model Furthermore, co-treatment with riluzole was performed determine any effects drug interactions potentially enhance preclinical research translation. shows ACY-738 treatment increased spinal cord mice, reduced neuron degeneration lumbar female ameliorated reduction peripheral nerve puncta size, but did overt decline. current also size partially restored after highlights importance measure Highlights inhibits leads mice. reduces restores decline Riluzole

Язык: Английский

Regulated cell death and its role in Alzheimer’s disease and amyotrophic lateral sclerosis DOI
Dietmar Rudolf Thal, Klara Gawor, Sebastiaan Moonen

и другие.

Acta Neuropathologica, Год журнала: 2024, Номер 147(1)

Опубликована: Апрель 7, 2024

Язык: Английский

Процитировано

22
Synaptic Dysfunction and Plasticity in Amyotrophic Lateral Sclerosis DOI Open Access
Rosario Gulino

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(5), С. 4613 - 4613

Опубликована: Фев. 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

Язык: Английский

Процитировано

21
Gap junction intercellular communications regulates activation of SARM1 and protects against axonal degeneration DOI Creative Commons
Wen Jie Zhu, Jun Liu,

Wan Hua Li

и другие.

Cell Death and Disease, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 14, 2025

Язык: Английский

Процитировано

0
Hypoxia-inducible factor 1 protects neurons from Sarm1-mediated neurodegeneration DOI Open Access
Paul Meraner, A. A. Avetisyan,

Kevin Swift

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 18, 2025

Abstract The Sarm1 NAD + hydrolase drives neurodegeneration in many contexts, but how activity is regulated remains poorly defined. Using CRISPR/Cas9 screening, we found loss of VHL suppressed Sarm1-mediated cellular degeneration. normally promotes O 2 -dependent constitutive ubiquitination and degradation hypoxia-inducible factor 1 (HIF-1), during hypoxia, HIF-1 stabilized regulates gene expression. We observed neuroprotection after depletion or other factors required for degradation, expression a non-ubiquitinated variant led to even stronger blockade axon degeneration mammals Drosophila . Neuroprotection DNA binding, prolonged expression, resulted broad changes. Unexpectedly, prevented the precipitous driven by activation neurons, despite being intrinsic TIR domain. Our work argues hypoxia inhibits through transcriptional changes, rendering neurons less sensitive when hypoxic state. Competing interests Marc Freeman co-founder Nura Bio, biotech startup pursuing novel neuroprotective therapies including SARM1 inhibition. remaining authors declare no competing interests.

Язык: Английский

Процитировано

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

V. A. Shiva Ayyadurai,

Prabhakar Deonikar,

Roger D. Kamm

и другие.

npj Systems Biology and Applications, Год журнала: 2025, Номер 11(1)

Опубликована: Март 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

Язык: Английский

Процитировано

0
The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) DOI Creative Commons
Jimmy Beckers, Philip Van Damme

Autophagy Reports, Год журнала: 2025, Номер 4(1)

Опубликована: Март 20, 2025

Язык: Английский

Процитировано

0
Sensory neuropathy in amyotrophic lateral sclerosis: a systematic review DOI Creative Commons
Alessandro Bombaci, Antonino Lupica, Federico Emanuele Pozzi

и другие.

Journal of Neurology, Год журнала: 2023, Номер 270(12), С. 5677 - 5691

Опубликована: Авг. 23, 2023

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of both upper and lower motoneurons, leading to motor non-motor symptoms. Recent evidence suggests that ALS indeed multisystem disorder, associated with cognitive impairment, dysautonomia, pain fatigue, excess secretions, sensory To evaluate whether neuropathy could broaden its spectrum, we systematically reviewed presence characteristics in ALS, extracting data on epidemiological, clinical, neurophysiological, neuropathological, genetic features. Sensory can be found up 20% patients, affecting large small fibers, although there great heterogeneity related different techniques used for detection (electromyography vs skin biopsy nerve biopsy). Moreover, association between CIDP-like needs better explored, it interpreted as part neuroinflammatory process latter disease. may spinal onset might more frequent SOD1 patients. seems mutually exclusive impairment. No associations sex other mutation were observed. All these literature reveal importance actively looking suggest including among features, explain symptoms frequently reported throughout course Its early identification help avoid diagnostic delays improve patients' treatment quality life.

Язык: Английский

Процитировано

11
The Corticospinal System and Amyotrophic Lateral Sclerosis: IFCN handbook chapter DOI Creative Commons
Roger Lemon

Clinical Neurophysiology, Год журнала: 2024, Номер 160, С. 56 - 67

Опубликована: Фев. 9, 2024

Corticospinal neurons located in motor areas of the cerebral neocortex project corticospinal axons which synapse with spinal network; a parallel corticobulbar system projects to cranial network and brainstem pathways. The primate has widespread cortical origin an extensive range different fibre diameters, including thick, fast-conducting axons. Direct cortico-motoneuronal (CM) projections from cortex arm hand alpha motoneurons are recent evolutionary feature, that is well developed dexterous primates particularly humans. Many these originate caudal subdivision area 4 ('new' M1: primary cortex). They arise varied soma size, those fast- relatively slow-conducting This CM been shown be involved control skilled movements, carried out fractionation distal extremities at low force levels. During movement, activated quite differently 'lower' motoneurons, there no simple or fixed functional relationship between so-called 'upper' motoneuron its target lower motoneuron. There key differences organisation function versus non-primates, such as rodents. These need recognized when making choice animal model for understanding disorders amyotrophic lateral sclerosis (ALS). In this neurodegenerative brain disease selective loss axons, their synaptic connections, reflected responses non-invasive stimuli measures cortico-muscular coherence. connections influencing limb muscles results differential muscle strength 'split-hand' phenotype. Importantly, also unique impairment coordination tasks require digit movement. Scores on validated tests could used assess progression.

Язык: Английский

Процитировано

4
Soma and neurite density imaging detects brain microstructural impairments in amyotrophic lateral sclerosis DOI
J. Y. Zeng, Hui‐Wei Huang,

Shao-Peng Zhuang

и другие.

European Journal of Radiology, Год журнала: 2025, Номер 184, С. 111981 - 111981

Опубликована: Фев. 5, 2025

Язык: Английский

Процитировано

0
Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances DOI Creative Commons
Qiu Jiang, Jie Liu, Shan Huang

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Март 10, 2025

Abstract In the context of global ageing, prevalence neurodegenerative diseases and dementia, such as Alzheimer’s disease (AD), is increasing. However, current symptomatic disease-modifying therapies have achieved limited benefits for in clinical settings. Halting progress neurodegeneration cognitive decline or even improving impaired cognition function are clinically meaningful goals treatments diseases. Ageing primary risk factor their associated comorbidities, vascular pathologies, elderly individuals. Thus, we aim to elucidate role ageing from perspective a complex system, which brain core peripheral organs tissues form holistic network support functions. During progressive deterioration structure entire body hampers its active adaptive responses various stimuli, thereby rendering individuals more vulnerable Consequently, propose that prevention treatment should be grounded antiageing rejuvenation means complemented by interventions targeting disease-specific pathogenic events. This integrated approach promising strategy effectively prevent, pause slow down progression

Язык: Английский

Процитировано

0