RNA Dysregulation in Neurodegeneration
Overview of Bhinge Lab research at the Living Systems Institute, University of Exeter
RNA dysregulation has emerged as a central theme in the pathogenesis of many neurodegenerative disorders with mutations in several RNA-binding proteins deemed to be directly involved in causing neuronal death. We are interested in how RNA regulation contributes to neuronal homeostasis and how its dysregulation leads to disease. The life of an RNA molecule is regulated at multiple levels. For example, transcription factors and the epigenetic machinery control transcriptional output, RNA-binding proteins control RNA splicing and trafficking, while microRNAs fine-tune translational output. Each of these players interact in a complex network that is cell-type specific to effect neuronal homeostasis. We believe that disruption of these cell-type specific networks leads to the differential susceptibility observed in neurodegenerative conditions. For example, Amyotrophic lateral sclerosis (ALS) is characterised by a preferential loss of motor neurons whereas certain cortical neuronal subtyes are affected in Fronto-temporal dementia (FTD) and Alzheimer's disease (AD).
We use neurons differentiated from patient-derived and genome-edited pluripotent stem cells to develop in vitro human models of ALS, FTD and AD. These models are further investigated using a combination of single-cell RNA-Seq, epigenomics and functional genetic screens including RNAi and CRISPRa.
The goal is to uncover disruptions in the epigenetic and non-coding RNA networks that lead to disease, to develop therapies aimed at halting the relentless neuronal loss.
CURRENT PROJECTS
RNA dysregulation due to TDP43 mislocalisation in motor and cortical neurons.
Disruption of microRNA networks in FUS and sporadic ALS.
Unbiased mapping of RNA-binding protein targets across the transcriptome.
Epigenetic mechanisms in C9ORF72 ALS.
EXTERNAL COLLABORATORS
Prof. Siddharthan Chandran, The University of Edinburgh, UK
Prof. Jernej Ule, The Francis Crick Institute, London, UK
Dr. Bhuvaneish T Selvaraj, The University of Edinburgh, UK
Prof. Gene Yeo, University of California San Diego, USA
Prof. Kevin Talbot, University of Oxford, UK
Dr. Asif Javed, The University of Hong Kong
Assoc. Prof. Olaf Ansorge, University of Oxford, UK
Prof. Aaron Gitler, Stanford University, USA
Dr. Vasanta Subramanian, University of Bath, UK
Assoc. Prof. Alessandro Rosa, Sapienza University of Rome, Italy
Dr. Jeremie Poschmann, INSERM, Université de Nantes, France
FUNDING
