Spliceosome integrity is defective in the motor neuron diseases ALS and SMA

Tsuiji, Hitomi; Iguchi, Yohei; Furuya, Asako; Kataoka, Ayane; Hatsuta, Hiroyuki; Atsuta, Naoki; Tanaka, Fumiaki; Hashizume, Yoshio; Akatsu, Hiroyasu; Murayama, Shigeo; Sobue, Gen; Yamanaka, Koji

doi:10.1002/emmm.201202303

Cited by 175 publications

(178 citation statements)

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“…It was recently shown that several proteins involved in amyotrophic lateral sclerosis, such as TDP43 and FUS, are important for gem formation (Shan et al, 2010;Kariya et al, 2012;Yamazaki et al, 2012;Tsuiji et al, 2013). As far we know, no mutation of U1-70K has been connected with amyotrophic lateral sclerosis to date (Finsterer and Burgunder, 2014).…”

Section: The U1-70k N-terminal Tail Is Important For Gem Integritymentioning

confidence: 99%

“…They often localize adjacent to Cajal bodies, the sites of snRNP modification and processing (Machyna et al, 2013). In addition to the SMN complex proteins, the only additional gem residents identified to date are 'fused in sarcoma' (FUS) and TDP-43, which are both involved in amyotrophic lateral sclerosis (Tsuiji et al, 2013). In addition, the loss of gems correlates with increased severity of spinal muscular atrophy and amyotrophic lateral sclerosis (Shan et al, 2010;Kariya et al, 2012;Achsel et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Splicing factor U1-70K interacts with the SMN complex and is required for nuclear Gem integrity

Stejskalová

Staněk

2014

Journal of Cell Science

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The nuclear SMN complex localizes to specific structures called nuclear gems. The loss of gems is a cellular marker for several neurodegenerative diseases. Here, we identify that the U1-snRNPspecific protein U1-70K localizes to nuclear gems, and we show that U1-70K is necessary for gem integrity. Furthermore, we show that the interaction between U1-70K and the SMN complex is RNA independent, and we map the SMN complex binding site to the unstructured N-terminal tail of U1-70K. Consistent with these results, the expression of the U1-70K N-terminal tail rescues gem formation. These findings show that U1-70K is an SMN-complexassociating protein, and they suggest a new function for U1-70K in the formation of nuclear gems.

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Section: The U1-70k N-terminal Tail Is Important For Gem Integritymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Splicing factor U1-70K interacts with the SMN complex and is required for nuclear Gem integrity

Stejskalová

Staněk

2014

Journal of Cell Science

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“…Further hypotheses on the etiology of SMA have emerged by (i) the observation that the SMN protein is localized in axons of motoneurons (Zhang et al 2003) and (ii) the identification of a number of RNA-binding proteins interacting with SMN such as hnRNP R and Q (Rossoll et al 2002), FMRP (Piazzon et al 2008), HuD (Fallini et al 2011), IMP1 (Fallini et al 2013) as well as TDP-43 (Wang et al 2002;Tsuiji et al 2013), and FUS (Yamazaki et al 2012). The latter two are implicated in ALS.…”

Section: Introductionmentioning

confidence: 99%

Subcellular transcriptome alterations in a cell culture model of spinal muscular atrophy point to widespread defects in axonal growth and presynaptic differentiation

Saal

Briese

Kneitz

et al. 2014

RNA

111

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Neuronal function critically depends on coordinated subcellular distribution of mRNAs. Disturbed mRNA processing and axonal transport has been found in spinal muscular atrophy and could be causative for dysfunction and degeneration of motoneurons. Despite the advances made in characterizing the transport mechanisms of several axonal mRNAs, an unbiased approach to identify the axonal repertoire of mRNAs in healthy and degenerating motoneurons has been lacking. Here we used compartmentalized microfluidic chambers to investigate the somatodendritic and axonal mRNA content of cultured motoneurons by microarray analysis. In axons, transcripts related to protein synthesis and energy production were enriched relative to the somatodendritic compartment. Knockdown of Smn, the protein deficient in spinal muscular atrophy, produced a large number of transcript alterations in both compartments. Transcripts related to immune functions, including MHC class I genes, and with roles in RNA splicing were up-regulated in the somatodendritic compartment. On the axonal side, transcripts associated with axon growth and synaptic activity were down-regulated. These alterations provide evidence that subcellular localization of transcripts with axonal functions as well as regulation of specific transcripts with nonautonomous functions is disturbed in Smn-deficient motoneurons, most likely contributing to the pathophysiology of spinal muscular atrophy.

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“…We would not be surprised if this effort eventually begins to impact motor neuron diseases more broadly. Indeed, the intersection of SMA and another common motor neuron disease, amyotrophic lateral sclerosis has already been reported [107][108][109]. Accordingly, we pose the following questions which we believe could define future SMA research.…”

Section: Perspectives On the Future Of Sma Researchmentioning

confidence: 92%

Spinal Muscular Atrophy: Journeying From Bench to Bedside

2014

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Spinal muscular atrophy (SMA) is a frequently fatal neuromuscular disorder and the most common inherited cause of infant mortality. SMA results from reduced levels of the survival of motor neuron (SMN) protein. Although the disease was first described more than a century ago, a precise understanding of its genetics was not obtained until the SMA genes were cloned in 1995. This was followed in rapid succession by experiments that assigned a role to the SMN protein in the proper splicing of genes, novel animal models of the disease, and the eventual use of the models in the pre clinical development of rational therapies for SMA. These successes have led the scientific and clinical communities to the cusp of what are expected to be the first truly promising treatments for the human disorder. Yet, important questions remain, not the least of which is how SMN paucity triggers a predominantly neuromuscular phenotype. Here we review how our understanding of the disease has evolved since the SMA genes were identified. We begin with a brief description of the genetics of SMA and the proposed roles of the SMN protein. We follow with an examination of how the genetics of the disease was exploited to develop genetically faithful animal models, and highlight the insights gained from their analysis. We end with a discussion of ongoing debates, future challenges, and the most promising treatments to have emerged from our current knowledge of the disease.

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Spliceosome integrity is defective in the motor neuron diseases ALS and SMA

Cited by 175 publications

References 50 publications

Splicing factor U1-70K interacts with the SMN complex and is required for nuclear Gem integrity

Splicing factor U1-70K interacts with the SMN complex and is required for nuclear Gem integrity

Subcellular transcriptome alterations in a cell culture model of spinal muscular atrophy point to widespread defects in axonal growth and presynaptic differentiation

Spinal Muscular Atrophy: Journeying From Bench to Bedside

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