Understanding neurodegenerative disease through studying RNA metabolism in neurons

Host: Dario Alessi

Venue: MSI Small Lecture Theatre, SLS

Abstract:

Proteinopathy of the RNA-binding protein TDP-43, defined by cytosolic aggregation and nuclear loss, is a hallmark of the fatal neurodegenerative diseases Amyotrophic Lateral Sclerosis (ALS) and fronto-temporal dementia (FTD), and emerging evidence suggests it may also contribute to Alzheimer's and Lewy body dementias.

 TDP-43 dysfunction causes cryptic splicing, where intronic sequences are aberrantly incorporated into mature RNA. Cryptic splicing signifies TDP-43 dysfunction post-mortem however, how cryptic splicing events affect disease progression is unknown.

 To understand the full extent of TDP-43’s cryptic splicing targets, I comprehensively analyzed cryptic splicing events regulated by TDP-43 in neuronal cell lines and in human post-mortem tissue. I identified hundreds of cryptic splicing targets specifically associated with TDP-43 proteinopathy, providing a strong basis for potential disease biomarkers and therapeutic targets. We discovered that while most cryptic splicing leads to destabilization of the RNA, some cryptic exons are translated and can be detected ante-mortem in ALS biofluids. Through these analyses, I also discovered the mechanism by which intronic ALS/FTLD risk and survival variants in the synaptic gene UNC13A exert their pathogenic effect through altering TDP-43 binding strength and thereby potentiating the inclusion of a destabilizing cryptic exon in UNC13A.

 To further explore how TPD-43 controls RNA stability, we performed the first ever transcriptome wide study of RNA stability after TDP-43 depletion in human neurons using the metabolic labelling technique SLAM-sequencing. Through the development of a novel computational analysis framework, I revealed a profound RNA destabilizing effect of TDP-43 depletion in human neurons.

RNA metabolism dysfunction in ALS is likely an important disease mechanism due to the preponderance of disease-causing mutations found in RNA-binding proteins, therefore is it critical to understand how RNA metabolism is regulated in the cells vulnerable in ALS, namely motor neurons. Therefore, using the techniques I developed to analyze metabolic labelling data, I will briefly touch on my work exploring the effects of the neurotrophic factor, brain-derived neurotrophic factor (BDNF) on the transcription rate of RNA in motor neurons.

 My research aims to explore the regulatory landscape of RNA metabolism in neurons, paving the way for novel therapeutic strategies combating neurodegenerative disease.

 Bio:

Dr. Anna-Leigh Brown received her B.Sc. in Cognitive Psychology and Neuroscience from Jacobs University Bremen in Germany in 2014. Following graduation, she moved to the National Institute of Mental Health in Bethesda, MD, USA where she researched auditory processing and attention. She then transitioned to industry as a data analyst before joining the National Center for Biotechnology Information in Bethesda, MD, USA, where she investigated DNA mutagenesis in cancer. Since 2019, Dr. Brown has been working in Dr. Pietro Fratta's lab at University College London, studying how RNA-binding proteins related to ALS regulate RNA metabolism and stability. In 2023, she received the Jean Corsan Prize for her research on the mechanisms of a genetic risk factor for both ALS and FTD. This work has opened new avenues for exploring the role of genetic variants in neurodegenerative diseases.