Active transport of the survival motor neuron protein and the role of exon-7 in cytoplasmic localization.
ABSTRACT Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by deletion and/or mutation of the survival motor neuron protein Gene (SMN1) that results in the expression of a truncated protein lacking the C terminal exon-7. Whereas SMN has been shown to be an important component of diverse ribonucleoprotein (RNP) complexes, its function in neurons is unknown. We hypothesize that the active transport of SMN may be important for neurite outgrowth and that disruption of exon-7 could impair its normal intracellular trafficking. SMN was localized in granules that were associated with cytoskeletal filament systems and distributed throughout neurites and growth cones. Live cell imaging of enhanced green fluorescent protein (EGFP)-SMN granules revealed rapid, bidirectional and cytoskeletal-dependent movements. Exon-7 was necessary for localization of SMN into the cytoplasm but was not sufficient for granule formation and transport. A cytoplasmic targeting signal within exon-7 was identified that could completely redistribute the nuclear protein D-box binding factor 1 into the cytoplasm. Neurons transfected with SMN lacking exon-7 had significantly shorter neurites, a defect that could be rescued by redirecting the exon-7 deletion mutant into neurites by a targeting sequence from growth-associated protein-43. These findings provide the first demonstration of cytoskeletal-based active transport of SMN in neuronal processes and the function of exon-7 in cytoplasmic localization. Such observations provide motivation to investigate possible transport defects or inefficiency of SMN associated RNPs in motor neuron axons in SMA.
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ABSTRACT: Spinal muscular atrophy (SMA) is an inherited neu-romuscular disorder pathologically characterized by the de-generation of motor neurons in the spinal cord and muscle atrophy. Motor neuron loss often results in severe muscle weakness causing affected infants to die before reaching 2 years of age. Patients with milder forms of SMA exhibit slow-ly progressive muscle weakness over many years. SMA is caused by the loss of SMN1 and the retention of at least 1 copy of a highly homologous SMN2. An alternative splicing event in the pre-mRNA arising from SMN2 results in the pro-duction of low levels of functional SMN protein. To date, there are no effective treatments available to treat patients with SMA. However, over the last 2 decades, the development of SMA mouse models and the identification of therapeutic tar-gets have resulted in a promising drug pipeline for SMA. Here, we highlight some of the therapeutic strategies that have been developed to activate SMN2 expression, modulate splic-ing of the SMN2 pre-mRNA, or replace SMN1 by gene ther-apy. After 2 decades of translational research, we now stand within reach of a treatment for SMA.Neurotherapeutics 01/2015; 12(2). DOI:10.1007/s13311-015-0337-y · 3.88 Impact Factor
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ABSTRACT: Spinal muscular atrophies (SMAs) are a group of inherited disorders characterized by motor neuron loss in the spinal cord and lower brainstem, muscle weakness, and atrophy. The clinical and genetic phenotypes incorporate a wide spectrum that is differentiated based on age of onset, pattern of muscle involvement, and inheritance pattern. Over the past several years, rapid advances in genetic technology have accelerated the identification of causative genes and provided important advances in understanding the molecular and biological basis of SMA and insights into the selective vulnerability of the motor neuron. Common pathophysiological themes include defects in RNA metabolism and splicing, axonal transport, and motor neuron development and connectivity. Together these have revealed potential novel treatment strategies, and extensive efforts are being undertaken towards expedited therapeutics. While a number of promising therapies for SMA are emerging, defining therapeutic windows and developing sensitive and relevant biomarkers are critical to facilitate potential success in clinical trials. This review incorporates an overview of the clinical manifestations and genetics of SMA, and describes recent advances in the understanding of mechanisms of disease pathogenesis and development of novel treatment strategies.Journal of the American Society for Experimental NeuroTherapeutics 11/2014; 12(2). DOI:10.1007/s13311-014-0314-x · 3.88 Impact Factor
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ABSTRACT: Motor neuron diseases, as the vast majority of neurodegenerative disorders in humans, are incurable conditions that are challenging to study in vitro, owing to the obstacles in obtaining the cell types majorly involved in the pathogenesis. Recent advances in stem cell research, especially in the development of induced pluripotent stem cell (iPSC) technology, have opened up the possibility of generating a substantial amount of disease-specific neuronal cells, including motor neurons and glial cells. The present review analyzes the practical implications of iPSCs, generated from fibroblasts of patients affected by spinal muscular atrophy (SMA), and discusses the challenges in the development and optimization of in vitro disease models. Research on patient-derived disease-specific cells may shed light on the pathological processes behind neuronal dysfunction and death in SMA, thus providing new insights for the development of novel effective therapies. Copyright © 2014. Published by Elsevier Inc.Molecular and Cellular Neuroscience 12/2014; 64. DOI:10.1016/j.mcn.2014.12.005 · 3.73 Impact Factor