Sex biology in amyotrophic lateral sclerosis

Zamani, Akram; Thomas, Emma; Wright, David K.

doi:10.1016/j.arr.2024.102228

Cited by 5 publications

(1 citation statement)

References 227 publications

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“…A similar gender bias has been reported in a mutated TARDBP -based ALS mouse model regarding changes in C-bouton numbers on fast or slow MNs (Bak et al, 2023 ). These observations could relate to the higher prevalence of ALS in men than in women (Zamani et al, 2024 ). Given that C-boutons increase MN excitability (Zagoraiou et al, 2009 ; Witts et al, 2014 ; Nascimento et al, 2020 ; Wells et al, 2021 ), an early increase in density and enlargement could contribute to MN hyperexcitability and participate in excitotoxic mechanisms leading to MN degeneration ( Figure 4 ).…”

Section: Alterations Of Spinal Cholinergic Pre-motor Insmentioning

confidence: 99%

Potential contribution of spinal interneurons to the etiopathogenesis of amyotrophic lateral sclerosis

Goffin,

Lemoine,

Clotman

2024

Front. Neurosci.

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Amyotrophic lateral sclerosis (ALS) consists of a group of adult-onset fatal and incurable neurodegenerative disorders characterized by the progressive death of motor neurons (MNs) throughout the central nervous system (CNS). At first, ALS was considered to be an MN disease, caused by cell-autonomous mechanisms acting specifically in MNs. Accordingly, data from ALS patients and ALS animal models revealed alterations in excitability in multiple neuronal populations, including MNs, which were associated with a variety of cellular perturbations such as protein aggregation, ribonucleic acid (RNA) metabolism defects, calcium dyshomeostasis, modified electrophysiological properties, and autophagy malfunctions. However, experimental evidence rapidly demonstrated the involvement of other types of cells, including glial cells, in the etiopathogenesis of ALS through non-cell autonomous mechanisms. Surprisingly, the contribution of pre-motor interneurons (INs), which regulate MN activity and could therefore critically modulate their excitability at the onset or during the progression of the disease, has to date been severely underestimated. In this article, we review in detail how spinal pre-motor INs are affected in ALS and their possible involvement in the etiopathogenesis of the disease.

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Section: Alterations Of Spinal Cholinergic Pre-motor Insmentioning

confidence: 99%

Potential contribution of spinal interneurons to the etiopathogenesis of amyotrophic lateral sclerosis

Goffin,

Lemoine,

Clotman

2024

Front. Neurosci.

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Micro‐Doses of DNP Preserve Motor and Muscle Function with a Period of Functional Recovery in Amyotrophic Lateral Sclerosis Mice

Zhong,

Dionela,

Kim

et al. 2024

Annals of Neurology

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ObjectiveMitochondrial dysfunction is one of the earliest pathological events observed in amyotrophic lateral sclerosis (ALS). The aim of this study is to evaluate the therapeutic efficacy of 2,4‐dinitrophenol (DNP), a mild mitochondrial uncoupler, in an ALS mouse model to provide preclinical proof‐of‐concept evidence of using DNP as a potential therapeutic drug for ALS.MethodshSOD1G93A mice were treated with 0.5–1.0 mg/kg DNP through daily oral gavage from presymptomatic stage or disease onset until 18 weeks old. Longitudinal behavioral studies were performed weekly or biweekly from 6 to 18 weeks old. In situ muscle contraction measurements in extensor digitorum longus muscles were conducted to evaluate the preservation of contractile force and motor unit numbers in hSOD1G93A mice following DNP treatment. Muscle innervation and inflammatory markers were assessed using immunostaining. Extent of protein oxidation and activation of Akt pathway were also examined.ResultsDNP delayed disease onset; improved motor coordination and muscle performance in vivo; preserved muscle contractile function, neuromuscular junction morphology, and muscle innervation; and reduced inflammation and protein oxidation at 18 weeks old in hSOD1G93A mice. Strikingly, symptomatic hSOD1G93A mice exhibited a period of recovery in running ability at 20 cm/s several weeks after 2,4‐dinitrophenol treatment started at disease onset, offering the first observation in disease phenotype reversal using a small molecule.InterpretationOur results strongly support that micro‐dose DNP may be used as a potential novel treatment for ALS patients, with a possibility for recovery, when used at optimal doses and time of intervention. ANN NEUROL 2024

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Two cardinal features of ALS, reduced STMN2 and pathogenic TDP-43, synergize to accelerate motor decline in mice

Krus,

Benitez,

Strickland

et al. 2025

Experimental Neurology

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Sex biology in amyotrophic lateral sclerosis

Cited by 5 publications

References 227 publications

Potential contribution of spinal interneurons to the etiopathogenesis of amyotrophic lateral sclerosis

Potential contribution of spinal interneurons to the etiopathogenesis of amyotrophic lateral sclerosis

Micro‐Doses of DNP Preserve Motor and Muscle Function with a Period of Functional Recovery in Amyotrophic Lateral Sclerosis Mice

Two cardinal features of ALS, reduced STMN2 and pathogenic TDP-43, synergize to accelerate motor decline in mice

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