Multiprotein complexes of the survival of motor neuron protein SMN with Gemins traffic to neuronal processes and growth cones of motor neurons.

Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Journal of Neuroscience (Impact Factor: 6.75). 09/2006; 26(33):8622-32. DOI: 10.1523/JNEUROSCI.3967-05.2006
Source: PubMed

ABSTRACT Spinal muscular atrophy (SMA), a progressive neurodegenerative disease affecting motor neurons, is caused by mutations or deletions of the SMN1 gene encoding the survival of motor neuron (SMN) protein. In immortalized non-neuronal cell lines, SMN has been shown to form a ribonucleoprotein (RNP) complex with Gemin proteins, which is essential for the assembly of small nuclear RNPs (snRNPs). An additional function of SMN in neurons has been hypothesized to facilitate assembly of localized messenger RNP complexes. We have shown that SMN is localized in granules that are actively transported into neuronal processes and growth cones. In cultured motor neurons, SMN granules colocalized with ribonucleoprotein Gemin proteins but not spliceosomal Sm proteins needed for snRNP assembly. Quantitative analysis of endogenous protein colocalization in growth cones after three-dimensional reconstructions revealed a statistically nonrandom association of SMN with Gemin2 (40%) and Gemin3 (48%). SMN and Gemin containing granules distributed to both axons and dendrites of differentiated motor neurons. A direct interaction between SMN and Gemin2 within single granules was indicated by fluorescence resonance energy transfer analysis of fluorescently tagged and overexpressed proteins. High-speed dual-channel imaging of live neurons depicted the rapid and bidirectional transport of the SMN-Gemin complex. The N terminus of SMN was required for the recruitment of Gemin2 into cytoplasmic granules and enhanced Gemin2 stability. These findings provide new insight into the molecular composition of distinct SMN multiprotein complexes in neurons and motivation to investigate deficiencies of localized RNPs in SMA.

  • [Show abstract] [Hide abstract]
    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. · 3.73 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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; · 3.88 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Spinal muscular atrophy (SMA) is one of the common neuromuscular disorders in children. In this review, the classification, phenotype, genetics, and management strategy for Chinese SMA patients are discussed, together with insights on new treatment modalities and prospective trials. SMA is an autosomal-recessive disorder with progressive muscle weakness and fatal outcome in many severely affected cases. Thus, identification of the otherwise healthy and asymptomatic carriers is of paramount importance toward prevention of the disease by prenatal diagnosis. Carrier testing among family members and even population screening should be advocated. Different methods of carrier testing to detect heterozygous deletion of the SMN1 gene, gene mutation, the 2'0 SMN1 genotype, and assessment of relative gene dosage of SMN1 and SMN2 are considered. Spinal muscular atrophy (SMA) is a hereditary disorder characterized by degeneration of the anterior horn cells. SMA was first reported by Hoffmann [1] and Werdnig [2], who described neonates with profound muscle wasting and flaccid paralysis. The gene locus was mapped to chromosome 5q11.2 Âq13.3 in 1995, and deletion or mutation in the survival motor neuron gene (SMN) was identified [3]. The diagnosis can be confirmed by genetic testing in most cases by determining the homozygous deletion or point mutation of the SMN1 gene (telomeric copy), thus avoiding the invasive muscle biopsy in clinically suspicious cases. The clinical severity is partly determined by the copy number of the SMN2 gene (centromeric copy) with an inverse relationship between copy number and disease severity. The SMN2 mRNA, which lacks Exon 7, results in a truncated and less stable protein; thus, methods to increase SMN2-derived protein production is an important focus for therapeutic trials [4].