Oligodendrocyte cytoskeletal dynamics and transport

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

This is the first year of our lab opening and we have pursued the following goals: 1. Lab set up and lab member recruitment. 2. Understanding the contribution of TPPP in neurological diseases. 3. Characterizing a mouse model in which mRNA transport in oligodendrocytes is defective. 4. Pursuing collaborations. 5. Writing reviews. Our lab set up and member recruitment are largely complete. I was appointed mid-October 2020 and our lab space became available in December 2020. Despite some initial administrative issues and supply delays due to COVID, I have received most of our large equipment purchases, including a microscope (via NIDA COAC), which we received this summer. In terms of lab composition, we currently have 1 research fellow, 1 postdoctoral IRTA fellow, and 2 postbac IRTA fellows. One postdoctoral IRTA fellow has successfully transitioned to a scientist position at the FDA with my support and recommendation. We anticipate that 1 predoc IRTA fellow and 1 visiting fellow (postdoc) will join before the end of the calendar year. On the TPPP project, we will pursue experiments at the molecular, cellular, and tissue level. We are currently looking at TPPP aggregation in human patient brains. This project was significantly delayed, because we received human brains 6 months after we initially requested them from the NIH NeuroBrainBank (a hub for several NIH-funded repositories). However, we are now in receipt of our initial request and have made striking observations of the aggregation pattern of TPPP in neurological disease. We plan to submit a manuscript detailing these results in Fall/Winter 2021. On the mRNA transport project, we are specifically looking at Mbp (myelin basic protein) as the mRNA cargo. Mbp is the most abundant mRNA in oligodendrocytes and encodes a locally translated protein that is found inside the myelin sheath. Our mouse model lacks the 3UTR region of Mbp mRNA (but contains the coding region) and was rederived by the NIMH transgenic core this spring. These animals display tremors 3 months of age and have profound motor deficits. We have completed electron microscopy analysis of both their central nervous system and peripheral nervous system myelin. We are also continuing to characterize Mbp mRNA transport using primary rodent oligodendrocyte cultures. Together, these data will show that mRNA transport is crucial for myelination in vivo. We plan to submit a manuscript on this set of experiments in Winter 2021. We have also been actively working on the following collaborations: 1. Damaris Lorenzo Lab (Univ. of North Carolina). We are working to understand whether the giant ANK2 isoform (440kDa) is expressed in oligodendrocytes. We have worked with the NINDS electron microscopy core to determine whether the giant-ANK2 knockout mouse has any myelin defects. We expect that this work will be published in Fall 2021. 2. Michael Ward Lab (NINDS). We are investigating mutations in patients that present with ALS-like disease. We hope to submit a manuscript in Fall/Winter 2021. Finally, we worked on two literature reviews. The first review on mRNA transport in glia was published in Trends in Cell Biology. The second review will focus on childhood leukodystrophies with genetic etiologies and their underlying molecular and cellular causes. We plan to submit this second review in Fall 2021.