SOD1 oligomers in amyotrophic lateral sclerosis

Choi, Esther; Dokholyan, Nikolay V.

doi:10.1016/j.sbi.2020.12.002

Cited by 23 publications

(21 citation statements)

References 51 publications

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“…The discovery of the connection between mutations in the SOD1 gene with certain forms of fALS made a tremendous impact in understanding the pathology of ALS. SOD1 mutations have been reported to contribute to ALS through not only protein misfolding and aggregation, but also proteasome impairment, oxidative stress, oligodendrocyte degeneration and mitochondrial dysfunction [ 76 , 77 ].…”

Section: Therapeutic Strategies For Als Targetsmentioning

confidence: 99%

Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis

Sever

Çi̇ftçi̇

DeMi̇rci̇

et al. 2022

IJMS

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Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating fatal neurodegenerative disorder, causing muscle atrophy and weakness, which leads to paralysis and eventual death. ALS has a multifaceted nature affected by many pathological mechanisms, including oxidative stress (also via protein aggregation), mitochondrial dysfunction, glutamate-induced excitotoxicity, apoptosis, neuroinflammation, axonal degeneration, skeletal muscle deterioration and viruses. This complexity is a major obstacle in defeating ALS. At present, riluzole and edaravone are the only drugs that have passed clinical trials for the treatment of ALS, notwithstanding that they showed modest benefits in a limited population of ALS. A dextromethorphan hydrobromide and quinidine sulfate combination was also approved to treat pseudobulbar affect (PBA) in the course of ALS. Globally, there is a struggle to prevent or alleviate the symptoms of this neurodegenerative disease, including implementation of antisense oligonucleotides (ASOs), induced pluripotent stem cells (iPSCs), CRISPR-9/Cas technique, non-invasive brain stimulation (NIBS) or ALS-on-a-chip technology. Additionally, researchers have synthesized and screened new compounds to be effective in ALS beyond the drug repurposing strategy. Despite all these efforts, ALS treatment is largely limited to palliative care, and there is a strong need for new therapeutics to be developed. This review focuses on and discusses which therapeutic strategies have been followed so far and what can be done in the future for the treatment of ALS.

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Section: Therapeutic Strategies For Als Targetsmentioning

confidence: 99%

Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis

Sever

Çi̇ftçi̇

DeMi̇rci̇

et al. 2022

IJMS

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“…SOD1 was the first gene identified in FALS and is involved in a great number of pathophysiological mechanisms [ 13 , 113 ]. Some mechanisms of disease implicated with SOD1, in both FALS and SALS, are protein misfolding, proteasome impairment, oxidative stress, oligodendrocyte degeneration and mitochondrial dysfunction [ 113 ]. Indeed, markers of oxidative damage were found in the central tissue (i.e., motor cortex and spinal cord) of both FALS and SALS patients [ 114 ].…”

Section: Protein Expression In Pbmcs Of Als Patientsmentioning

confidence: 99%

Biomarkers in Human Peripheral Blood Mononuclear Cells: The State of the Art in Amyotrophic Lateral Sclerosis

Pansarasa¹,

Scarian

Dragoni

et al. 2022

IJMS

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the progressive loss of lower motor neurons, weakness and muscle atrophy. ALS lacks an effective cure and diagnosis is often made by exclusion. Thus, it is imperative to search for biomarkers. Biomarkers can help in understanding ALS pathomechanisms, identification of targets for treatment and development of effective therapies. Peripheral blood mononuclear cells (PBMCs) represent a valid source for biomarkers compared to cerebrospinal fluid, as they are simple to collect, and to plasma, because of the possibility of detecting lower expressed proteins. They are a reliable model for patients’ stratification. This review provides an overview on PBMCs as a potential source of biomarkers in ALS. We focused on altered RNA metabolism (coding/non-coding RNA), including RNA processing, mRNA stabilization, transport and translation regulation. We addressed protein abnormalities (aggregation, misfolding and modifications); specifically, we highlighted that SOD1 appears to be the most characterizing protein in ALS. Finally, we emphasized the correlation between biological parameters and disease phenotypes, as regards prognosis, severity and clinical features. In conclusion, even though further studies are needed to standardize the use of PBMCs as a tool for biomarker investigation, they represent a promising approach in ALS research.

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“…In this sense, deciphering the mechanisms of protein misfolding and the role of misfolded protein is key to understanding pivotal aspects of ALS pathomechanisms. Interestingly, recent research has attributed soluble misfolded proteins as the toxic player in neurodegeneration rather than the large aggregates (Kirkitadze et al, 2002;Urushitani et al, 2006;Proctor et al, 2016;Choi and Dokholyan, 2021), implying a protective mechanistic role of large aggregates (Zhu et al, 2018). The toxic mechanism of soluble misfolded proteins is unknown, but major cellular processes include dysfunctional RNA metabolism, impaired proteostasis, mitochondrial dysfunction, and excitotoxicity (Ruegsegger and Saxena, 2016;Butti and Patten, 2019;Calió et al, 2020;Gunes et al, 2020).…”

Section: Amyotrophic Lateral Sclerosis Molecular and Genetic Characte...mentioning

confidence: 99%

Motor neuron-derived induced pluripotent stem cells as a drug screening platform for amyotrophic lateral sclerosis

Amorós

Choi

Cofré

et al. 2022

Front. Cell Dev. Biol.

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The development of cell culture models that recapitulate the etiology and features of nervous system diseases is central to the discovery of new drugs and their translation onto therapies. Neuronal tissues are inaccessible due to skeletal constraints and the invasiveness of the procedure to obtain them. Thus, the emergence of induced pluripotent stem cell (iPSC) technology offers the opportunity to model different neuronal pathologies. Our focus centers on iPSCs derived from amyotrophic lateral sclerosis (ALS) patients, whose pathology remains in urgent need of new drugs and treatment. In this sense, we aim to revise the process to obtain motor neurons derived iPSCs (iPSC-MNs) from patients with ALS as a drug screening model, review current 3D-models and offer a perspective on bioinformatics as a powerful tool that can aid in the progress of finding new pharmacological treatments.

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SOD1 oligomers in amyotrophic lateral sclerosis

Cited by 23 publications

References 51 publications

Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis

Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis

Biomarkers in Human Peripheral Blood Mononuclear Cells: The State of the Art in Amyotrophic Lateral Sclerosis

Motor neuron-derived induced pluripotent stem cells as a drug screening platform for amyotrophic lateral sclerosis

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