Cellular bases of the RNA metabolism dysfunction in motor neurons of a murine model of spinal muscular atrophy: Role of Cajal bodies and the nucleolus

Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder mainly caused by deletions or mutations of one gene, Survival Motor Neuron (SMN). SMN is crucial in splicing processes for proper gene expression. Previous studies showed a significant decrease in the levels of minor splicing (U12 intron) snRNPs in SMA mice and a restoration of a U12 intron-containing gene partially rescued disease phenotypes in SMA animal models. Here we utilized viral delivery system to investigate the potential effect of increasing minor splicing snRNAs on SMN deficiency. We introduced minor splicing snRNAs, human U11 and U12, or human U11, U12 with U4atac to the well-characterized SMA mice. Our treatment prolonged survival and increased percent peak weight gain. The motor function was improved however NMJ pathology was largely uncorrected. Nonetheless, the increment of minor splicing snRNAs maintained the number of central synapses on motor neurons. Furthermore, no changes in SMN expression after the treatment indicated that increasing minor splicing snRNAs partially benefits disease phenotypes independent to SMN expression in SMA mice. Furthermore, defects in U12-intron splicing events were partially corrected for U12 intron-containing SMN target gene, Stasimon, reiterating the improvement of minor splicing in SMA mice. Taken together, our results showed the restoration of minor splicing snRNAs partially ameliorates SMN deficiency caused phenotypes, indicating that U12-dependent minor splicing event is responsible for the disease progress of SMA.

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Reorganization of Cajal bodies and nucleolar targeting of coilin in motor neurons of type I spinal muscular atrophy

Histochemistry and Cell Biology ◽

10.1007/s00418-012-0921-8 ◽

2012 ◽

Vol 137 (5) ◽

pp. 657-667 ◽

Cited By ~ 27

Author(s):

Olga Tapia ◽

Rocío Bengoechea ◽

Ana Palanca ◽

Rosa Arteaga ◽

J. Fernando Val-Bernal ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neurons ◽

Muscular Atrophy ◽

Cajal Bodies ◽

Type I

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Tissue-specific models of spinal muscular atrophy confirm a critical role of SMN in motor neurons from embryonic to adult stages

Human Molecular Genetics ◽

10.1093/hmg/ddw044 ◽

2016 ◽

Vol 25 (9) ◽

pp. 1728-1738 ◽

Cited By ~ 14

Author(s):

Angela S. Laird ◽

Nikolce Mackovski ◽

Silke Rinkwitz ◽

Thomas S. Becker ◽

Jean Giacomotto

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neurons ◽

Muscular Atrophy ◽

Critical Role ◽

Tissue Specific

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RNA Is a Double-Edged Sword in ALS Pathogenesis

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.708181 ◽

2021 ◽

Vol 15 ◽

Author(s):

Benjamin L. Zaepfel ◽

Jeffrey D. Rothstein

Keyword(s):

Motor Neurons ◽

Cortical Neurons ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Rna Metabolism ◽

Small Subset ◽

Toxic Rna ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that affects upper and lower motor neurons. Familial ALS accounts for a small subset of cases (<10–15%) and is caused by dominant mutations in one of more than 10 known genes. Multiple genes have been causally or pathologically linked to both ALS and frontotemporal dementia (FTD). Many of these genes encode RNA-binding proteins, so the role of dysregulated RNA metabolism in neurodegeneration is being actively investigated. In addition to defects in RNA metabolism, recent studies provide emerging evidence into how RNA itself can contribute to the degeneration of both motor and cortical neurons. In this review, we discuss the roles of altered RNA metabolism and RNA-mediated toxicity in the context of TARDBP, FUS, and C9ORF72 mutations. Specifically, we focus on recent studies that describe toxic RNA as the potential initiator of disease, disease-associated defects in specific RNA metabolism pathways, as well as how RNA-based approaches can be used as potential therapies. Altogether, we highlight the importance of RNA-based investigations into the molecular progression of ALS, as well as the need for RNA-dependent structural studies of disease-linked RNA-binding proteins to identify clear therapeutic targets.

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AN AYURVEDIC MANAGEMENT OF SPINAL MUSCULAR ATROPHY (SMA) – A CASE STUDY

November 2020 - International Ayurvedic Medical Journal ◽

10.46607/iamj4309112021 ◽

2021 ◽

Vol 9 (11) ◽

pp. 2897-2902

Author(s):

Raheena B ◽

Shaila Borannavar ◽

Ananta S Desai

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neurons ◽

Autosomal Recessive ◽

Muscular Atrophy ◽

Genetic Disorder ◽

The Body ◽

Erect Posture ◽

Smn1 Gene ◽

Autosomal Recessive Pattern

Spinal Muscular Atrophy (SMA) is the second leading genetic disorder inherited in the autosomal recessive pattern due to the absence of the SMN1 gene characterized by loss of motor neurons and progressive muscle wasting, often leading to dependent life and decreased life span. In Ayurveda, this condition can be considered as Kulaja Vyadhi wherein the patient’s Mamsa and Snayu is affected by Vata. This can be regarded as Mamsa-Snayugata Sarvanga Vata. It is said that Prakruta Vata dosha is the life, it is the strength, it is the sustainer of the body, it holds the body and life together. If it is Vikruta it produces Sankocha, Khanja, Kubjatva, Pangutva, Khalli and Soshana of Anga. So, in this disease aggravated Vata does the vitiation of Mamsa and Snayu thus leading to Soshana of both, resulting in Stambha, Nischalikarana of Avayava. A 21years female patient was admitted to our I.P.D with c/o of reduced strength in all four limbs leading to the inability to walk and to maintain erect posture during standing and sitting positions. Based on Ayurvedic principles the patient was initially subjected to Avaranahara Chikitsa followed by Brimhana line of management. Keywords: Mamsagata vata, Snayugata vata, Sarvanga vata, Spinal muscular atrophy (SMA)

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Multifaceted roles of microRNAs: From motor neuron generation in embryos to degeneration in spinal muscular atrophy

eLife ◽

10.7554/elife.50848 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 2

Author(s):

Tai-Heng Chen ◽

Jun-An Chen

Keyword(s):

Nervous System ◽

Neurodegenerative Diseases ◽

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Motor Neurons ◽

Muscular Atrophy ◽

Cell Types ◽

Spinal Motor Neurons ◽

Potential Applications ◽

The Central Nervous System

Two crucial questions in neuroscience are how neurons establish individual identity in the developing nervous system and why only specific neuron subtypes are vulnerable to neurodegenerative diseases. In the central nervous system, spinal motor neurons serve as one of the best-characterized cell types for addressing these two questions. In this review, we dissect these questions by evaluating the emerging role of regulatory microRNAs in motor neuron generation in developing embryos and their potential contributions to neurodegenerative diseases such as spinal muscular atrophy (SMA). Given recent promising results from novel microRNA-based medicines, we discuss the potential applications of microRNAs for clinical assessments of SMA disease progression and treatment.

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