Molecular Factors Involved in Spinal Muscular Atrophy Pathways as Possible Disease-modifying Candidates

Maretina, Marianna; Zheleznyakova, Galina Yurevna; Lanko, Kristina; Egorova, Anna; Baranov, V. S.; Kiselev, Anton

doi:10.2174/1389202919666180101154916

Cited by 31 publications

(24 citation statements)

References 203 publications

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“…SMN protein reduction causes cellular changes which directly or indirectly provoke the deregulation of several processes involved in cell homeostasis, including autophagy and apoptosis 31 . Nonetheless, intracellular pathways related to neurotrophic communication or calcium regulation may be impaired in SMA pathology and contribute to modifying the evolution of the disease 32 . In this context, we have previously demonstrated that treating SMA mice with the calpain inhibitor calpeptin had a positive effect on survival and motor function 21 .…”

Section: Discussionmentioning

confidence: 99%

Calpain system is altered in survival motor neuron-reduced cells from in vitro and in vivo spinal muscular atrophy models

et al. 2020

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Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by loss of the survival motor neuron 1 (SMN1) gene. SMA is characterized by the degeneration of spinal cord motoneurons (MNs), progressive skeletal muscle atrophy, and weakness. The cellular and molecular mechanisms causing MN loss of function are only partially known. Recent advances in SMA research postulate the role of calpain protease regulating survival motor neuron (SMN) protein and the positive effect on SMA phenotype of treatment with calpain inhibitors. We analyzed the level of calpain pathway members in mice and human cellular SMA models. Results indicate an increase of calpain activity in SMN-reduced MNs. Spinal cord analysis of SMA mice treated with calpeptin, a calpain inhibitor, showed an increase of SMN, calpain, and its endogenous inhibitor calpastatin in MNs. Finally, in vitro calpeptin treatment prevented microtubule-associated protein 1A/1B-light chain 3 (LC3) increase in MNs neurites, indicating that calpain inhibition may reduce autophagosome accumulation in neuron prolongations, but not in soma. Thus, our results show that calpain activity is increased in SMA MNs and its inhibition may have a beneficial effect on SMA phenotype through the increase of SMN in spinal cord MNs.

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Section: Discussionmentioning

confidence: 99%

Calpain system is altered in survival motor neuron-reduced cells from in vitro and in vivo spinal muscular atrophy models

et al. 2020

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“…Spinal Muscular Atrophy (SMA) is a monogenic neuromuscular syndrome triggered due to mutations in Survival of motor neurone 1 (SMN1) gene (Maretina et al, 2018). The SMA patients maintain in situ copy of the paralog SMN2 gene, which produces reduced amounts of the SMN protein.…”

Section: Effects Of Hdaci In Various Neurodegenerative Disorders Modementioning

confidence: 99%

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

2020

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Histone deacetylases (HADC) are the enzymes that remove acetyl group from lysine residue of histones and non-histone proteins and regulate the process of transcription by binding to transcription factors and regulating fundamental cellular process such as cellular proliferation, differentiation and development. In neurodegenerative diseases, the histone acetylation homeostasis is greatly impaired, shifting towards a state of hypoacetylation. The histone hyperacetylation produced by direct inhibition of HDACs leads to neuroprotective actions. This review attempts to elaborate on role of small molecule inhibitors of HDACs on neuronal differentiation and throws light on the potential of HDAC inhibitors as therapeutic agents for treatment of neurodegenerative diseases. The role of HDACs in neuronal cellular and disease models and their modulation with HDAC inhibitors are also discussed. Significance of these HDAC inhibitors has been reviewed on the process of neuronal differentiation, neurite outgrowth and neuroprotection regarding their potential therapeutic application for treatment of neurodegenerative diseases.

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“…We believe that in terms of its impact on SMA phenotype, SMN2 copy number might be considered as the tip of an iceberg of which other genetic and epigenetic features, most notably SNVs, represent the submerged part with relevant effects to phenotype of the patients with SMA (figure). A number of other genes have been proposed as candidate modifiers of the SMA phenotype including methylation status of SMN2 (reviewed in Maretina et al, 2018), 39 although none of them are yet validated in clinical practice. Given that SMN2 variants modify the disease phenotype and that transcripts derived from SMN2 are targets for splicing modifiers in the therapeutic scenario, it is essential to gain a thorough insight into the complete SMN2 sequences of discordant patients.…”

Section: Yesmentioning

confidence: 99%

Practical guidelines to manage discordant situations of SMN2 copy number in patients with spinal muscular atrophy

et al. 2020

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ObjectiveAssessment of SMN2 copy number in patients with spinal muscular atrophy (SMA) is essential to establish careful genotype-phenotype correlations and predict disease evolution. This issue is becoming crucial in the present scenario of therapeutic advances with the perspective of SMA neonatal screening and early diagnosis to initiate treatment, as this value is critical to stratify patients for clinical trials and to define those eligible to receive medication. Several technical pitfalls and interindividual variations may account for reported discrepancies in the estimation of SMN2 copy number and establishment of phenotype-genotype correlations.MethodsWe propose a management guide based on a sequence of specified actions once SMN2 copy number is determined for a given patient. Regardless of the method used to estimate the number of SMN2 copies, our approach focuses on the manifestations of the patient to recommend how to proceed in each case.ResultsWe defined situations according to SMN2 copy number in a presymptomatic scenario of screening, in which we predict the possible evolution, and when a symptomatic patient is genetically confirmed. Unexpected discordant cases include patients having a single SMN2 copy but noncongenital disease forms, 2 SMN2 copies compatible with type II or III SMA, and 3 or 4 copies of the gene showing more severe disease than expected.ConclusionsOur proposed guideline would help to systematically identify discordant SMA cases that warrant further genetic investigation. The SMN2 gene, as the main modifier of SMA phenotype, deserves a more in-depth study to provide more accurate genotype-phenotype correlations.

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Molecular Factors Involved in Spinal Muscular Atrophy Pathways as Possible Disease-modifying Candidates

Cited by 31 publications

References 203 publications

Calpain system is altered in survival motor neuron-reduced cells from in vitro and in vivo spinal muscular atrophy models

Calpain system is altered in survival motor neuron-reduced cells from in vitro and in vivo spinal muscular atrophy models

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

Practical guidelines to manage discordant situations of SMN2 copy number in patients with spinal muscular atrophy

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