Motoneuron death in normal and spinal muscular atrophy-affected human fetuses

Fidziańska, Anna; Rafałowska, J

doi:10.1007/s00401-002-0566-0

Cited by 35 publications

(9 citation statements)

References 15 publications

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“…Based on these observations, we considered that the morphological defect of NMJ-LS in our culture was due to functional impairments of the MNs in target pathfinding and/or in inducing or maintaining AChR clustering, rather than due to motor neuronal loss. Considering that the formation and maintenance of NMJs has been indicated to precede the occurrence of MN death even in humans, as mentioned above, the vulnerability of MNs in SMA patients seems to be due not only to the autonomous cell susceptibility to various stresses, but also as a consequence of the NMJ defect, which causes the impairment of neurotrophic factors and subsequent death of MNs ( Fidziańska and Rafalowska, 2002; Fischer et al., 2004 ).…”

Section: Discussionmentioning

confidence: 99%

Modeling the Early Phenotype at the Neuromuscular Junction of Spinal Muscular Atrophy Using Patient-Derived iPSCs

et al. 2015

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SummarySpinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations of the survival of motor neuron 1 (SMN1) gene. In the pathogenesis of SMA, pathological changes of the neuromuscular junction (NMJ) precede the motor neuronal loss. Therefore, it is critical to evaluate the NMJ formed by SMA patients’ motor neurons (MNs), and to identify drugs that can restore the normal condition. We generated NMJ-like structures using MNs derived from SMA patient-specific induced pluripotent stem cells (iPSCs), and found that the clustering of the acetylcholine receptor (AChR) is significantly impaired. Valproic acid and antisense oligonucleotide treatment ameliorated the AChR clustering defects, leading to an increase in the level of full-length SMN transcripts. Thus, the current in vitro model of AChR clustering using SMA patient-derived iPSCs is useful to dissect the pathophysiological mechanisms underlying the development of SMA, and to evaluate the efficacy of new therapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

Modeling the Early Phenotype at the Neuromuscular Junction of Spinal Muscular Atrophy Using Patient-Derived iPSCs

et al. 2015

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“…Interestingly, abnormal copy numbers (1 or 3) of Smn1 have also been found in 12% of patients with sporadic ALS as compared to 4.5% in the wider population[35]. Histologic studies of human fetuses with homozygous deletions of the Smn1 gene have found the nuclei of motor neurons to be frequently small and unusually shaped [36]. In addition, like in ALS, observations from studies of SMA mutant mice have revealed a large accumulation of neurofilaments in the presynaptic terminals.…”

Section: Spinal Muscular Atrophymentioning

confidence: 99%

The BMP signaling pathway at the Drosophila neuromuscular junction and its links to neurodegenerative diseases

Bayat

Jaiswal

Bellen

2011

Current Opinion in Neurobiology

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Summary The Drosophila neuromuscular junction (NMJ) has recently provided new insights into the roles of various proteins in neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), Multiple Sclerosis (MS) Hereditary Spastic Paraplegia (HSP), and Huntington’s Disease (HD). Several developmental signaling pathways including WNT, MAPK and BMP/TGF-β signaling play important roles in the formation and growth of the Drosophila NMJ. Studies of the fly homologues of genes that cause neurodegenerative disease at the NMJ have resulted in a better understanding of the roles of these proteins in vivo. These studies may shed light on the pathological mechanisms of these diseases, with implications for reduced BMP/TGF-β signaling in ALS, SMA and HD and increased signaling in HSP and MS.

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“…Morphological studies of motor neurons in SMA Type I fetuses gave evidence that programmed motoneuron death is prolonged in comparison with controls (Fidzianska & Rafalowska, ; Soler‐Botija et al. ).…”

Section: Introductionmentioning

confidence: 99%

“…). Nuclear abnormalities were found as early as 16 weeks' gestation in affected fetuses (Fidzianska & Rafalowska, ). More recent neuro‐pathological analyses of affected fetuses and patients suggest a fetal developmental maturation error and a postnatal retrograde dying‐back degeneration of lower motor neurons in SMA (Ito et al.…”

Section: Introductionmentioning

confidence: 99%

Spinal muscular atrophy: a motor neuron disorder or a multi‐organ disease?

2013

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Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is the leading genetic cause of infantile death. SMA is characterized by loss of motor neurons in the ventral horn of the spinal cord, leading to weakness and muscle atrophy. SMA occurs as a result of homozygous deletion or mutations in Survival Motor Neuron-1 (SMN1). Loss of SMN1 leads to a dramatic reduction in SMN protein, which is essential for motor neuron survival. SMA disease severity ranges from extremely severe to a relatively mild adult onset form of proximal muscle atrophy. Severe SMA patients typically die mostly within months or a few years as a consequence of respiratory insufficiency and bulbar paralysis. SMA is widely known as a motor neuron disease; however, there are numerous clinical reports indicating the involvement of additional peripheral organs contributing to the complete picture of the disease in severe cases. In this review, we have compiled clinical and experimental reports that demonstrate the association between the loss of SMN and peripheral organ deficiency and malfunction. Whether defective peripheral organs are a consequence of neuronal damage/ muscle atrophy or a direct result of SMN loss will be discussed.

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Motoneuron death in normal and spinal muscular atrophy-affected human fetuses

Cited by 35 publications

References 15 publications

Modeling the Early Phenotype at the Neuromuscular Junction of Spinal Muscular Atrophy Using Patient-Derived iPSCs

Modeling the Early Phenotype at the Neuromuscular Junction of Spinal Muscular Atrophy Using Patient-Derived iPSCs

The BMP signaling pathway at the Drosophila neuromuscular junction and its links to neurodegenerative diseases

Spinal muscular atrophy: a motor neuron disorder or a multi‐organ disease?

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