SMN and Gemins: ‘We are family’ … or are we?

Cauchi, Ruben J.

doi:10.1002/bies.201000088

Cited by 89 publications

(72 citation statements)

References 120 publications

(192 reference statements)

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“…GEMIN4 contributes to the processing of pre-miRNA by introducing the miRNA precursor into the RISC (Murashov et al, 2007). GEMIN4 is a core member of the survival of motor neurons (SMN) complex, which is a protein involved in the assembly of small nuclear ribonucleic particles (Cauchi, 2010). A lack of SMN results in widespread splicing defects, especially in spinal motor neurons, and is one cause of spinal muscular atrophy (Charroux et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Long-term exposure to black carbon, cognition and single nucleotide polymorphisms in microRNA processing genes in older men

Colicino

Giuliano

Power

et al. 2016

Environment International

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Introduction Air pollution exposure has been linked to impaired cognitive aging, but little is known about biomarkers modifying this association. MicroRNAs (miRNAs) control gene expression and neuronal programming. MiRNA levels vary due to single nucleotide polymorphisms (SNPs) in genes processing miRNAs from precursor molecules. Objectives To investigate whether SNPs in miRNA-processing genes are associated with cognition and modify the relationship between black carbon (BC), marker of traffic-related pollution, and cognitive functions. Methods 533 Normative Aging Study men (mean±SD 72±7 years) were tested ≤4 times (mean=1.7 times) using seven cognitive tests between 1995–2007. We tested interactions of 16 miRNA-related SNPs with 1-year average BC from a validated land-use-regression model. We used covariate-adjusted logistic regression for low (≤ 25) Mini-Mental State Examination (MMSE) and mixed-effect regression for a global cognitive score combining six other tests. Results Global cognition was negatively associated with the homozygous minor variant of rs595961 AGO1 (−0.42SD; 95%CI: (−0.71, −0.13)) relative to the major variant. BC-MMSE association was stronger in heterozygous carriers of rs11077 XPO5 (OR=1.99; 95%CI: (1.39, 2.85)) and minor variant carriers of GEMIN4 rs2740348 (OR=1.34; 95%CI: (1.05, 1.7)), compared to their major variant. The BC-global-cognition association was stronger in heterozygous carriers of GEMIN4 rs4968104 (−0.10SD; 95%CI: (−0.18, −0.02)), and GEMIN4 rs910924 (−0.09SD; 95%CI: (−0.17, −0.02)) relative to the major variant. Blood miRNA expression analyses showed associations only of XPO5 rs11077 with miR-9 and miR-96. Conclusions Carriers of particular miRNA-processing SNPs had higher susceptibility to BC in BC-cognition associations, possibly due to influences on miRNA expression.

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Section: Discussionmentioning

confidence: 99%

Long-term exposure to black carbon, cognition and single nucleotide polymorphisms in microRNA processing genes in older men

Colicino

Giuliano

Power

et al. 2016

Environment International

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“…Complexity was gained in evolution through the incorporation of the remaining constituents (Kroiss et al, 2008; Cauchi, 2010). The fruit fly Drosophila melanogaster possesses a minimalistic complex that, in addition to SMN and Gemin2, also includes Gemin3 and Gemin5 (Cauchi et al, 2010).…”

Section: Anatomy Of the Smn-gemins Complex Chaperone Machinementioning

confidence: 99%

“…pICln and Tgs1 are two factors that are known to have a leading role in the early and late phase of snRNP assembly, respectively. Importantly, unlike the Gemins (reviewed in Cauchi, 2010), they have never been directly linked to the assembly and transport of messenger ribonucleoprotein (mRNP) complexes along axons, which is often considered as the primary non-canonical activity of the SMN-Gemins complex (reviewed in Donlin-Asp et al, 2016). …”

Section: In Vivo Studies Linking Snrnp Assembly Defects To Neuromuscumentioning

confidence: 99%

Spinal Muscular Atrophy: From Defective Chaperoning of snRNP Assembly to Neuromuscular Dysfunction

Lanfranco

Vassallo

Cauchi

2017

Front. Mol. Biosci.

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Spinal Muscular Atrophy (SMA) is a neuromuscular disorder that results from decreased levels of the survival motor neuron (SMN) protein. SMN is part of a multiprotein complex that also includes Gemins 2–8 and Unrip. The SMN-Gemins complex cooperates with the protein arginine methyltransferase 5 (PRMT5) complex, whose constituents include WD45, PRMT5 and pICln. Both complexes function as molecular chaperones, interacting with and assisting in the assembly of an Sm protein core onto small nuclear RNAs (snRNAs) to generate small nuclear ribonucleoproteins (snRNPs), which are the operating components of the spliceosome. Molecular and structural studies have refined our knowledge of the key events taking place within the crowded environment of cells and the numerous precautions undertaken to ensure the faithful assembly of snRNPs. Nonetheless, it remains unclear whether a loss of chaperoning in snRNP assembly, considered as a “housekeeping” activity, is responsible for the selective neuromuscular phenotype in SMA. This review thus shines light on in vivo studies that point toward disturbances in snRNP assembly and the consequential transcriptome abnormalities as the primary drivers of the progressive neuromuscular degeneration underpinning the disease. Disruption of U1 snRNP or snRNP assembly factors other than SMN induces phenotypes that mirror aspects of SMN deficiency, and splicing defects, described in numerous SMA models, can lead to a DNA damage and stress response that compromises the survival of the motor system. Restoring the correct chaperoning of snRNP assembly is therefore predicted to enhance the benefit of SMA therapeutic modalities based on augmenting SMN expression.

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“…SMN-1 is part of a protein complex that controls the assembly of small nuclear ribonucleoproteins (snRNPs) essential for pre-mRNA splicing (Fallini et al, 2012; Liu et al, 1997). It is not clear whether this function or an alternative function is crucial for SMA pathogenesis (Cauchi, 2010). For instance, SMN-1 localizes to myofilaments in Drosophila flight muscles, where it regulates actin dynamics (Rajendra et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The secreted MSP domain of C. elegans VAPB homolog VPR-1 patterns the adult striated muscle mitochondrial reticulum via SMN-1

et al. 2017

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The major sperm protein domain (MSPd) has an extracellular signaling function implicated in amyotrophic lateral sclerosis. Secreted MSPds derived from the C. elegans VAPB homolog VPR-1 promote mitochondrial localization to actin-rich I-bands in body wall muscle. Here we show that the nervous system and germ line are key MSPd secretion tissues. MSPd signals are transduced through the CLR-1 Lar-like tyrosine phosphatase receptor. We show that CLR-1 is expressed throughout the muscle plasma membrane, where it is accessible to MSPd within the pseudocoelomic fluid. MSPd signaling is sufficient to remodel the muscle mitochondrial reticulum during adulthood. An RNAi suppressor screen identified survival of motor neuron 1 (SMN-1) as a downstream effector. SMN-1 acts in muscle, where it colocalizes at myofilaments with ARX-2, a component of the Arp2/3 actin-nucleation complex. Genetic studies suggest that SMN-1 promotes Arp2/3 activity important for localizing mitochondria to I-bands. Our results support the model that VAPB homologs are circulating hormones that pattern the striated muscle mitochondrial reticulum. This function is crucial in adults and requires SMN-1 in muscle, likely independent of its role in pre-mRNA splicing.

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SMN and Gemins: ‘We are family’ … or are we?

Cited by 89 publications

References 120 publications

Long-term exposure to black carbon, cognition and single nucleotide polymorphisms in microRNA processing genes in older men

Long-term exposure to black carbon, cognition and single nucleotide polymorphisms in microRNA processing genes in older men

Spinal Muscular Atrophy: From Defective Chaperoning of snRNP Assembly to Neuromuscular Dysfunction

The secreted MSP domain of C. elegans VAPB homolog VPR-1 patterns the adult striated muscle mitochondrial reticulum via SMN-1

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