TDP-43 in nuclear condensates in health, stress and neurodegenerative disease

Hosts: Dr Leeanne McGurk & Dr Raja Nirujogi

Venue: MSI Small Lecture Theatre, SLS

Summary: TDP-43 protein is ubiquitously deregulated in neurodegenerative diseases of aging, which often have a multifactorial nature and extrinsic stressors as a trigger/second hit. TDP-43 undergoes reversible nuclear condensation in stressed cells, including neurons. In the first part of my talk, I will introduce our recent study which characterised these TDP-43 condensates and identified determinants of their assembly and dissolution, in particular, the pivotal role of RNA. Furthermore, we found, using a novel confocal nanoscanning assay, that amyotrophic lateral sclerosis (ALS)-causative mutations alter TDP-43 condensation properties by changing its RNP affinity. Studies into the downstream effects of TDP-43 condensation revealed wide-spread splicing alterations in human motor neurons. Moreover, stress-induced splicing changes in TDP-43 targets were especially prominent and persisting for STMN2 RNA leading to rapid and persisting STMN2 protein depletion. In the second part of my talk, I will introduce a novel optogenetic platform for modelling aggregation pathology of ALS-causative C9ORF72 dipeptide repeat (DPR) proteins. Using this approach, we identified modifiers of DPR aggregation in cellular models and demonstrated that nuclear DPR aggregation causes TDP-43 condensation independent of stress response. These studies offer a model of the evolution of DPR pathology in ALS and shed light on the initial stages of disease development preceding the onset of cytoplasmic pathology. Overall, our results point to early pathological changes to TDP-43 in the nucleus and support therapeutic targeting of its condensation and stress response in ALS.

Bio: After graduating with an MSc degree in Genetics in 2008, I pursued a PhD in Biochemistry which I completed in 2012. During my PhD training, supported by an EMBO fellowship, I contributed to the generation and characterisation of a unique mouse model of a fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS); report on this mouse model published in J Biol Chem was selected as Paper of the Year. I continued to develop this stream of research during my postdoctoral training at Cardiff University (Prof Buchman’s lab), where I spearheaded several projects focussing on (dys)metabolism of ribonucleoprotein (RNP) granules in ALS. In 2015, these studies were supported by a 3-year fellowship from the Medical Research Foundation. In 2018, I was awarded a 4-year senior non-clinical fellowship from the MND Association and started my own group at the Medicines Discovery Institute, a newly established Cardiff University’s translational unit. During my time at the MDI, my research was supported by AMS Springboard award, the ISSF Translational Kick-Start award and funding from Welsh Government. I am the recipient of the ENCALS Young Investigator award 2020. In September 2021, I moved to SITraN, University of Sheffield, to continue studies into the molecular pathogenesis of ALS and related disorders within a world-leading centre for neurodegenerative disease research. In May 2022, I was awarded the UKRI Future Leaders Fellowship to establish a research programme entitled “RNA-protein complexes in health and disease and their therapeutic targeting”. The group is also funded by MNDA, BBSRC, MRC and MND Scotland as well as an MRC/AstraZeneca partnership grant and has a strong translational focus on developing RNA/RNP targeted small molecule therapeutics. Group webpage: https://www.ts-lab.co.uk/

Venue: MSI Small Lecture Theatre, SLS

Summary: TDP-43 protein is ubiquitously deregulated in neurodegenerative diseases of aging, which often have a multifactorial nature and extrinsic stressors as a trigger/second hit. TDP-43 undergoes reversible nuclear condensation in stressed cells, including neurons. In the first part of my talk, I will introduce our recent study which characterised these TDP-43 condensates and identified determinants of their assembly and dissolution, in particular, the pivotal role of RNA. Furthermore, we found, using a novel confocal nanoscanning assay, that amyotrophic lateral sclerosis (ALS)-causative mutations alter TDP-43 condensation properties by changing its RNP affinity. Studies into the downstream effects of TDP-43 condensation revealed wide-spread splicing alterations in human motor neurons. Moreover, stress-induced splicing changes in TDP-43 targets were especially prominent and persisting for STMN2 RNA leading to rapid and persisting STMN2 protein depletion. In the second part of my talk, I will introduce a novel optogenetic platform for modelling aggregation pathology of ALS-causative C9ORF72 dipeptide repeat (DPR) proteins. Using this approach, we identified modifiers of DPR aggregation in cellular models and demonstrated that nuclear DPR aggregation causes TDP-43 condensation independent of stress response. These studies offer a model of the evolution of DPR pathology in ALS and shed light on the initial stages of disease development preceding the onset of cytoplasmic pathology. Overall, our results point to early pathological changes to TDP-43 in the nucleus and support therapeutic targeting of its condensation and stress response in ALS.

Bio: After graduating with an MSc degree in Genetics in 2008, I pursued a PhD in Biochemistry which I completed in 2012. During my PhD training, supported by an EMBO fellowship, I contributed to the generation and characterisation of a unique mouse model of a fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS); report on this mouse model published in J Biol Chem was selected as Paper of the Year. I continued to develop this stream of research during my postdoctoral training at Cardiff University (Prof Buchman’s lab), where I spearheaded several projects focussing on (dys)metabolism of ribonucleoprotein (RNP) granules in ALS. In 2015, these studies were supported by a 3-year fellowship from the Medical Research Foundation. In 2018, I was awarded a 4-year senior non-clinical fellowship from the MND Association and started my own group at the Medicines Discovery Institute, a newly established Cardiff University’s translational unit. During my time at the MDI, my research was supported by AMS Springboard award, the ISSF Translational Kick-Start award and funding from Welsh Government. I am the recipient of the ENCALS Young Investigator award 2020. In September 2021, I moved to SITraN, University of Sheffield, to continue studies into the molecular pathogenesis of ALS and related disorders within a world-leading centre for neurodegenerative disease research. In May 2022, I was awarded the UKRI Future Leaders Fellowship to establish a research programme entitled “RNA-protein complexes in health and disease and their therapeutic targeting”. The group is also funded by MNDA, BBSRC, MRC and MND Scotland as well as an MRC/AstraZeneca partnership grant and has a strong translational focus on developing RNA/RNP targeted small molecule therapeutics. Group webpage: https://www.ts-lab.co.uk/