Biology subjects

Goodchild, R. E.

Publications and source records attributed to Goodchild, R. E..

3 recordsLinked to original sources

bioRxiv2020

The Torsin/ NEP1R1-CTDNEP1/ Lipin axis regulates nuclear envelope lipid metabolism for nuclear pore complex insertion

Torsin ATPases of the endoplasmic reticulum (ER) and nuclear envelope (NE) lumen inhibit Lipin-mediated phosphatidate (PA) to diacylglycerol (DAG) conversion by an unknown mechanism. This excess PA metabolism is implicated in TOR1A/TorsinA diseases, but it is unclear whether it explains why Torsin concomitantly affects nuclear structure, lipid droplets (LD), organelle and cell growth. Here a fly miniscreen identified that Torsins affect these events via the NEP1R1-CTDNEP1 phosphatase complex. Further, Torsin homo-oligomerization rather than ATPase activity was key to function. NEP1R1-CTDNEP1 activates Lipin by dephosphorylation. We show that Torsin prevents CTDNEP1 from accumulating in the NE and excludes Lipin from the nucleus. Moreover, this repression of nuclear PA metabolism is required for interphase nuclear pore biogenesis. We conclude that Torsin is an upstream regulator of the NEP1R1-CTDNEP1/ Lipin pathway. This connects the ER/NE lumen with PA metabolism, and affects numerous cellular events including it has a previously unrecognized role in nuclear pore biogenesis.HighlightsNuclear envelope PA-DAG-TAG synthesis is independently regulated by Torsin and Torip/LAP1Torsin removes CTDNEP1 from the nuclear envelope and excludes Lipin from the nucleusExcess nuclear envelope NEP1R1-CTDNEP1/ Lipin activity impairs multiple aspects of NPC biogenesisNEP1R1-CTDNEP1/ Lipin inhibition prevents cellular defects associated with TOR1A and TOR1AIP1 / LAP1 diseaseCompeting Interest StatementThe authors have declared no competing interest.View Full Text

cell biology↗

bioRxiv2020

Lipid metabolic stress in development defines which genetically-susceptible DYT-TOR1A mice develop disease

There has been enormous progress defining the genetic landscape of disease. However, genotypes rarely fully predict neurological phenotypes, and we rarely understand why. TOR1A +/{Delta}gag that causes dystonia with ~30% penetrance is a classic case. Here we show, in inbred mice, that +/{Delta}gag affects embryonic brain lipid metabolism with sex-skewed reduced penetrance. Penetrance is affected by environmental context, including maternal diet. The lipid metabolic defect resolves during post-natal development. Nevertheless, we discover dystonia-like symptoms in ~30% of juvenile female Tor1a+/{Delta}gag mice, and prevent these symptoms by genetically suppressing abnormal lipid metabolism. We conclude that Tor1a+/{Delta}gag embryos poorly buffer metabolic stress in utero, resulting in a period of abnormal metabolism that hardwires the brain for dystonia in later life. The data show unexpected and profound impacts of sex, and thus highlight the importance of examining male and female animal models of disease. Significance StatementThe genetic landscape of neurological disease is relatively well mapped. However, we typically cannot explain why some mutations only cause disease in a subset of individuals. A classic case is DYT-TOR1A dystonia that only develops in 30% of TOR1A+/{Delta}gag carriers. We now find that ~30% of inbred female Tor1a+/{Delta}gag mice develop abnormal brain lipid metabolism as embryos, while males are spared. The percentage is affected by maternal diet. Further, this period of abnormal lipid metabolism causes dystonia-like symptoms in juvenile mice. These data show how an environmentally-sensitive event of development defines which genetically-susceptible individuals develop disease in later life. They also highlight the importance of examining male and female animal models of disease.

neuroscience↗

bioRxiv2019

Inhibition of Lipin lipid phosphatase hyperactivity rescues TorsinA neurological disease

TOR1A/TorsinA mutations cause poorly explained neurological diseases. A dominantly inherited mutation causes isolated dystonia, while biallelic mutations cause a recessive infant-onset syndrome with cases of lethality. Here we report an unexpected connection between lipid metabolism and these diseases. Lipin phosphatidic acid phosphatase activity was abnormally regulated in TorsinA dystonia patient cells, and in the brains of three different TorsinA disease model mice. Lipin activity was causative to symptoms given that lowering Lipin1 in vivo strongly intervened against lethality in disease mice. Furthermore, Lipin hyperactivity caused cell death in vitro, and Lipin1 deficiency suppressed neurodegeneration in vivo. In addition, it protected the striatal cholinergic interneurons that are implicated in TorsinA movement disorders, and concomitantly suppressed abnormal motor behaviors of TorsinA mice. These data establish the central role of Lipin lipid enzyme hyperactivity in TorsinA disease and show that Lipin inhibition is a therapeutic target for these incurable conditions.\n\nOne Sentence SummaryLipin inhibition rescues TorsinA neurological disease

genetics↗