COPI transport complexes bind to specific RNAs in neuronal cells

Todd, Adrian G.; Lin, Hai; Ebert, Allison D.; Liu, Yunlong; Androphy, Elliot J.

doi:10.1093/hmg/dds480

Cited by 40 publications

(29 citation statements)

References 51 publications

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“…Autophagy dysfunction is implicated in ALS and in degradation of mSOD1 and mTDP-43 [9], but the underlying mechanisms remain unclear. RNA dysfunction is now widely implicated in ALS and ER-derived vesicles are involved in RNA trafficking [74]. Furthermore, Ypt1 binds to HAC1 RNA and modulates the UPR [75].…”

Section: Discussionmentioning

confidence: 99%

Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS

et al. 2015

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Several diverse proteins are linked genetically/pathologically to neurodegeneration in amyotrophic lateral sclerosis (ALS) including SOD1, TDP-43 and FUS. Using a variety of cellular and biochemical techniques, we demonstrate that ALS-associated mutant TDP-43, FUS and SOD1 inhibit protein transport between the endoplasmic reticulum (ER) and Golgi apparatus in neuronal cells. ER-Golgi transport was also inhibited in embryonic cortical and motor neurons obtained from a widely used animal model (SOD1(G93A) mice), validating this mechanism as an early event in disease. Each protein inhibited transport by distinct mechanisms, but each process was dependent on Rab1. Mutant TDP-43 and mutant FUS both inhibited the incorporation of secretory protein cargo into COPII vesicles as they bud from the ER, and inhibited transport from ER to the ER-Golgi intermediate (ERGIC) compartment. TDP-43 was detected on the cytoplasmic face of the ER membrane, whereas FUS was present within the ER, suggesting that transport is inhibited from the cytoplasm by mutant TDP-43, and from the ER by mutant FUS. In contrast, mutant SOD1 destabilised microtubules and inhibited transport from the ERGIC compartment to Golgi, but not from ER to ERGIC. Rab1 performs multiple roles in ER-Golgi transport, and over-expression of Rab1 restored ER-Golgi transport, and prevented ER stress, mSOD1 inclusion formation and induction of apoptosis, in cells expressing mutant TDP-43, FUS or SOD1. Rab1 also co-localised extensively with mutant TDP-43, FUS and SOD1 in neuronal cells, and Rab1 formed inclusions in motor neurons of spinal cords from sporadic ALS patients, which were positive for ubiquitinated TDP-43, implying that Rab1 is misfolded and dysfunctional in sporadic disease. These results demonstrate that ALS-mutant forms of TDP-43, FUS, and SOD1 all perturb protein transport in the early secretory pathway, between ER and Golgi compartments. These data also imply that restoring Rab1-mediated ER-Golgi transport is a novel therapeutic target in ALS.

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Section: Discussionmentioning

confidence: 99%

Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS

et al. 2015

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“…Any reads less than 35 bases were discarded. Our experience suggested that this strategy effectively eliminated low‐quality reads while high‐quality regions were retained …”

Section: Methodsmentioning

confidence: 99%

“…Our experience suggested that this strategy effectively eliminated low-quality reads while high-quality regions were retained. [45][46][47] Sequence alignment. The BFAST (http://bfast.sourceforge.net) 48 was used as the primary alignment algorithm because it has high sensitivity for aligning reads on loci containing small insertions and deletions compared to the reference genome (hg19).…”

Section: Measurement Of Mrna Expressionmentioning

confidence: 99%

Age‐Related Changes in MicroRNA Expression and Pharmacogenes in Human Liver

Burgess

Philips

Benson

et al. 2015

Clin Pharma and Therapeutics

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Developmental changes in the liver can significantly impact drug disposition. Due to the emergence of microRNAs (miRNAs) as important regulators of drug disposition gene expression, we studied age-dependent changes in miRNA expression. Expression of 533 miRNAs was measured in 90 human liver tissues (fetal, pediatric (1-17 years), and adult (28-80 years); n=30 each). 114 miRNAs were upregulated and 72 were downregulated from fetal to pediatric, and 2 and 3, respectively, from pediatric to adult. Among the developmentally changing miRNAs, 99 miRNA-mRNA interactions were predicted or experimentally validated (e.g. hsamiR-125b-5p-CYP1A1; hsa-miR-34a-5p-HNF4A). In human liver samples (n=10 each), analyzed by RNA-sequencing, significant negative correlations were observed between the expression of >1000 miRNAs and mRNAs of drug disposition and regulatory genes. Our data suggest a mechanism for the marked changes in hepatic gene expression between the fetal and pediatric developmental periods, and support a role for these age-dependent miRNAs in regulating drug disposition.

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“…Any read with a length of less than 35 bases was discarded. Our experience suggests that this strategy effectively eliminates low-quality reads while retaining high-quality regions (Breese and Liu, 2013;Juan et al, 2013;Todd et al, 2013).…”

Section: Bioinformatic Analysis Of the Rna-seq Datamentioning

confidence: 99%

Regulation of MicroRNA Expression by Rifampin in Human Hepatocytes

et al. 2013

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Rifampin causes drug interactions by altering hepatic drug metabolism. Because microRNAs (miRNAs) have been shown to regulate genes involved in drug metabolism, we determined the effect of rifampin on the expression of hepatic miRNAs. Primary human hepatocytes from seven subjects were treated with rifampin, and the expression of miRNA and cytochrome P450 (P450) mRNAs was measured by TaqMan assays and RNA-seq, respectively. Rifampin induced the expression of 10 clinically important and 13 additional P450 genes and repressed the expression of 9 other P450 genes (P < 0.05). Rifampin induced the expression of 33 miRNAs and repressed the expression of 35 miRNAs (P < 0.05). Several of these changes were highly negatively correlated with the rifampin-induced changes in the expression of their predicted target P450 mRNAs, supporting the possibility of miRNA-induced regulation of P450 mRNA expression. In addition, several other miRNA changes were positively correlated with the changes in P450 mRNA expression, suggesting similar regulatory mechanisms. Despite the interindividual variability in the rifampin effects on miRNA expression, principal components analysis clearly separated the rifampin-treated samples from the controls. In conclusion, rifampin treatment alters miRNA expression patterns in human hepatocytes, and some of the changes were correlated with the rifampin-induced changes in expression of the P450 mRNAs they are predicted to target.

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COPI transport complexes bind to specific RNAs in neuronal cells

Cited by 40 publications

References 51 publications

Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS

Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS

Age‐Related Changes in MicroRNA Expression and Pharmacogenes in Human Liver

Regulation of MicroRNA Expression by Rifampin in Human Hepatocytes

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