Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Biomarkers, and Therapeutic Strategies

Yang, Xiaoming; Ji, Yanan; Wang, Wei; Zhang, Lilei; Chen, Zehao; Yu, Miaomei; Shen, Yuntian; Ding, Fei; Gu, Xiaosong; Sun, Hualin

doi:10.3390/antiox10071012

Cited by 40 publications

(38 citation statements)

References 193 publications

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“…Gene editing, using the CRISPR/Cas9 technology, has been implemented for SOD1 and C9ORF72 repeats expansions with promising results in patients-derived cells and animal models. Clinical trials are currently underway to test the efficacy of these approaches in ALS patients (Amado and Davidson, 2021 ; Yang et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Antibody-Based Therapeutic Interventions for Amyotrophic Lateral Sclerosis: A Systematic Literature Review

2021

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Amyotrophic Lateral Sclerosis (ALS) is a mid-life onset neurodegenerative disease that manifests its symptomatology with motor impairments and cognitive deficits overlapping with Frontotemporal Lobar Degeneration (FTLD). The etiology of ALS remains elusive, with various mechanisms and cellular targets implicated, and no treatment can reverse or stop the progression of the pathology. Therapeutic interventions based on passive immunization are gaining attention for neurodegenerative diseases, and FDA recently approved the first antibody-based approach for Alzheimer's disease. The present systematic review of the literature aims to highlight the efforts made over the past years at developing antibody-based strategies to cure ALS. Thirty-one original research papers have been selected where the therapeutic efficacy of antibodies were investigated and described in patients and animal models of ALS. Antibody-based interventions analyzed, target both extracellular molecules implicated in the pathology and intracellular pathogenic proteins known to drive the disease, such as SOD1, TDP-43 or C9ORF72 repeats expansions. The potentials and limitations of these therapeutic interventions have been described and discussed in the present review.

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Section: Introductionmentioning

confidence: 99%

Antibody-Based Therapeutic Interventions for Amyotrophic Lateral Sclerosis: A Systematic Literature Review

2021

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“…In addition to denervation caused by peripheral nerve injury, aging, paralysis, malnutrition, a variety of diseases including cancer, cardiovascular disease, and neurodegenerative diseases can all cause skeletal muscle atrophy (24)(25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

An analysis of lncRNA-miRNA-mRNA networks to investigate the effects of HDAC4 inhibition on skeletal muscle atrophy caused by peripheral nerve injury

Gu¹,

Lin²,

Li³

et al. 2022

Ann Transl Med

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Background: Muscle atrophy caused by peripheral nerve injury is a common clinical disease, with no effective treatments currently available. Our previous studies have found that denervation-induced muscle atrophy can be alleviated by inhibiting histone deacetylase 4 (HDAC4). An increasing amount of evidence shows that microRNA (miRNA) and long noncoding RNA (lncRNA) are involved in the occurrence of muscle atrophy. This study aimed to find the mechanism by which HDAC4 regulates denervation-induced muscle atrophy based on lncRNA-associated competing endogenous RNA (ceRNA) networks. Methods:We analyzed the influence of short hairpin RNA (shRNA) knockdown of HDAC4 on lncRNAs and miRNAs after denervated muscle atrophy using RNA sequencing. A Pearson's correlation heat map and principal component analysis were employed to analyze differentially expressed miRNAs and lncRNAs.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses of target genes were conducted. The ceRNA network of lncRNA-miRNA-mRNA was constructed, and the core regulatory molecules in the ceRNA network were analyzed.Results: We found 32 miRNAs and 111 lncRNAs related to denervated muscle atrophy regulated by HDAC4. Moreover, 15 downregulated lncRNAs, 14 upregulated miRNAs, and 61 downregulated messenger RNAs (mRNAs) constituted a ceRNA regulatory network, participating in the biological processes including response to denervation involved in regulation of muscle adaptation, along with the signaling pathways including autophagy, FoxO signaling pathways, and Jak-STAT signaling pathways. Additionally, 6 upregulated lncRNAs, 8 downregulated miRNAs, and 66 upregulated mRNAs constituted another ceRNA regulatory network, which was mainly involved in cell cycle-related biological processes and pathways.Finally, 3 lncRNAs, 4 miRNAs, and 12 mRNAs constituted a ceRNA sub-network, and XR_377582.2 and ENSMUST00000143649 were considered to be the key lncRNAs.Conclusions: In the ceRNA network, all nodes are directly or indirectly involved in the process by which HDAC4 regulates skeletal muscle atrophy caused by peripheral nerve injury. XR_377582.2 and ENSMUST00000143649 may be the key lncRNAs related to HDAC4 involved in the regulation of muscle atrophy.

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“…To predict disease development, some of the above-mentioned molecules can be used as biomarkers. Mentioned markers from the group of RNA-binding proteins in ALS are TDP-43, FUS, or hnRNPs, although some others can be used-TATA-box binding protein associated factor 15 (TAF15), which is mutated in both SALS and FALS; Ewing Sarcoma breakpoint region 1/EWS RNA binding protein 1 (EWSR1) with similar characteristics as FUS and TAF15 that they can easily aggregate leading to the toxicityn [133]; or ataxin-2 (ATXN2), which acts as a dose-sensitive modifier of TDP-43 toxic effect [134]. From the group of ALS-related genes, we could highlight SOD1, C9orf72, or spastacsin (SPG) [133], as well as non-coding RNA such as microRNA, circular RNA [133], or other molecules.…”

Section: Molecular Biomarkers Of Alsmentioning

confidence: 99%

“…Mentioned markers from the group of RNA-binding proteins in ALS are TDP-43, FUS, or hnRNPs, although some others can be used-TATA-box binding protein associated factor 15 (TAF15), which is mutated in both SALS and FALS; Ewing Sarcoma breakpoint region 1/EWS RNA binding protein 1 (EWSR1) with similar characteristics as FUS and TAF15 that they can easily aggregate leading to the toxicityn [133]; or ataxin-2 (ATXN2), which acts as a dose-sensitive modifier of TDP-43 toxic effect [134]. From the group of ALS-related genes, we could highlight SOD1, C9orf72, or spastacsin (SPG) [133], as well as non-coding RNA such as microRNA, circular RNA [133], or other molecules. It is worth mentioning serum uric acid, whose serum levels negatively correlate with the risk of death in patients with ALS [135]; the detection of higher levels of chitotriosidase in CSF correlates with microglial activation in the white matter of the spinal cord and may be helpful in patients with a short history of symptoms that are difficult to identify [136].…”

Section: Molecular Biomarkers Of Alsmentioning

confidence: 99%

Molecular Pathology of ALS: What We Currently Know and What Important Information Is Still Missing

Jankovska

Matěj

2021

Diagnostics

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Despite an early understanding of amyotrophic lateral sclerosis (ALS) as a disease affecting the motor system, including motoneurons in the motor cortex, brainstem, and spinal cord, today, many cases involving dementia and behavioral disorders are reported. Therefore, we currently divide ALS not only based on genetic predisposition into the most common sporadic variant (90% of cases) and the familial variant (10%), but also based on cognitive and/or behavioral symptoms, with five specific subgroups of clinical manifestation—ALS with cognitive impairment, ALS with behavioral impairment, ALS with combined cognitive and behavioral impairment, the fully developed behavioral variant of frontotemporal dementia in combination with ALS, and comorbid ALS and Alzheimer’s disease (AD). Generally, these cases are referred to as amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD). Clinical behaviors and the presence of the same pathognomonic deposits suggest that FTLD and ALS could be a continuum of one entity. This review was designed primarily to compare neuropathological findings in different types of ALS relative to their characteristic locations as well as the immunoreactivity of the inclusions, and thus, foster a better understanding of the immunoreactivity, distribution, and morphology of the pathological deposits in relation to genetic mutations, which can be useful in specifying the final diagnosis.

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Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Biomarkers, and Therapeutic Strategies

Cited by 40 publications

References 193 publications

Antibody-Based Therapeutic Interventions for Amyotrophic Lateral Sclerosis: A Systematic Literature Review

Antibody-Based Therapeutic Interventions for Amyotrophic Lateral Sclerosis: A Systematic Literature Review

An analysis of lncRNA-miRNA-mRNA networks to investigate the effects of HDAC4 inhibition on skeletal muscle atrophy caused by peripheral nerve injury

Molecular Pathology of ALS: What We Currently Know and What Important Information Is Still Missing

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