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

Spinal muscular atrophy (SMA) is a childhood neuromuscular disorder caused by depletion of the survival motor neuron (SMN) protein. SMA is characterized by the selective death of spinal cord motor neurons, leading to progressive muscle wasting. Loss of skeletal muscle in SMA is a combination of denervation-induced muscle atrophy and intrinsic muscle pathologies. Elucidation of the pathways involved is essential to identify the key molecules that contribute to and sustain muscle pathology. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TNF receptor superfamily member fibroblast growth factor inducible 14 (Fn14) pathway has been shown to play a critical role in the regulation of denervation-induced muscle atrophy as well as muscle proliferation, differentiation and metabolism in adults. However, it is not clear whether this pathway would be important in highly dynamic and developing muscle. We thus investigated the potential role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn-/-;SMN2 and the less severe Smn2B/- SMA mice, which undergo a progressive neuromuscular decline in the first three post-natal weeks. Here, we report significantly dysregulated expression of the TWEAK/Fn14 pathway during disease progression in skeletal muscle of the two SMA mouse models. In addition, siRNA-mediated Smn knockdown in C2C12 myoblasts suggests a genetic interaction between Smn and the TWEAK/Fn14 pathway. Further analyses of SMA, Tweak-/- and Fn14-/- mice revealed dysregulated myopathy, myogenesis and glucose metabolism pathways as a common skeletal muscle feature, and providing further evidence in support of a relationship between the TWEAK/Fn14 pathway and Smn. Finally, a pharmacological intervention (Fc-TWEAK) to upregulate the activity of the TWEAK/Fn14 pathway improved disease phenotypes in the two SMA mouse models. Our study provides novel mechanistic insights into the molecular players that contribute to muscle pathology in SMA and into the role of the TWEAK/Fn14 pathway in developing muscle.

Download Full-text

Examine the role of minor splicing pathway in spinal muscular atrophy

10.32469/10355/48228 ◽

2014 ◽

Author(s):

◽

Pei-Fen Yen

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neurons ◽

Muscular Atrophy ◽

Autosomal Recessive Disorder ◽

Potential Effect ◽

Survival Motor Neuron ◽

Disease Phenotypes ◽

Peak Weight ◽

Central Synapses

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.

Download Full-text

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)

Download Full-text

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.

Download Full-text

Green kiwifruit extracts protect motor neurons from death in a spinal muscular atrophy model in Caenorhabditis elegans

Food Science & Nutrition ◽

10.1002/fsn3.1078 ◽

2019 ◽

Vol 7 (7) ◽

pp. 2327-2335

Author(s):

Nadia Mazzarella ◽

Ivana Giangrieco ◽

Serena Visone ◽

Pamela Santonicola ◽

Jannis Achenbach ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Spinal Muscular Atrophy ◽

Motor Neurons ◽

Muscular Atrophy ◽

Green Kiwifruit

Download Full-text

Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

Journal of Experimental Neuroscience ◽

10.4137/jen.s33122 ◽

2016 ◽

Vol 10 ◽

pp. JEN.S33122 ◽

Cited By ~ 36

Author(s):

Saif Ahmad ◽

Kanchan Bhatia ◽

Annapoorna Kannan ◽

Laxman Gangwani

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Motor Neurons ◽

Molecular Mechanisms ◽

Muscular Atrophy ◽

Survival Motor Neuron ◽

Skeletal Muscle Atrophy ◽

Spinal Motor Neurons ◽

Low Levels ◽

Smn Protein

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA.

Download Full-text