Friday, April 30, 2021

Neurology/Neuroscience Research Seminar

12:00 PM to 1:00 PM

CME credit available, click here

Virtual event

Zoom ID: 910 4550 7427 Passcode: 776945

The RNA binding protein TDP-43 represents a major marker of pathology, with ~97% of ALS cases exhibiting cytoplasmic inclusions that contain TDP-43. TDP-43 has been shown to induce toxicity through both nuclear loss- and cytoplasmic gain-of-function mechanisms. Indeed, when mislocalized from the nucleus to the cytoplasm, TDP-43 associates with a plethora of RNA containing complexes including stress and transport granules as well as protein complexes devoid of RNA. TDP-43 has also been shown to influence the translation of specific mRNAs, both as a negative and as a positive regulator. Taken together these findings suggest  a complex role for TDP-43 in translation regulation, which may be related to the formation of TDP-43 cytoplasmic puncta in disease and altered protein expression and/or localization of its mRNA targets. A potential mechanism by which TDP-43 dysregulates translation is by altering the ribosomes’ access to mRNAs, as suggested by the previously proposed “ribostasis hypothesis”. Further substantiating this model are recent reports of TDP-43 translational targets including futsch and hsc70-4 mRNAs (in axons) and Rac1 mRNA (in dendrites), all of which were identified through candidate approaches. Using a combination of RNA immunoprecipitations and ribosomal tagging approaches in Drosophila we recently identified several mRNAs whose association with ribosomes is altered in motor neurons, in flies and patient tissues. I will discuss the relationship between TDP-43 associated mRNAs and translation in disease and TDP-43 dependent metabolic alterations some of which result from RNA processing defects.

“Come Fly With Me - What Drosophila Can Tell Us About TDP-43 Proteinopathies"

Daniela C. Zarnescu, PhD

Associate Professor Molecular and Cellular Biology College of Medicine Tuscon