Project - Exploring the brain transcriptome in FTD using bulk and single-nuclei sequencing
All Chief investigators and associate investigators
John Mattick, Glenda Halliday, Clement Loy and Sandy Pineda Gonzalaz
Research Project Abstract
Frontotemporal dementia (FTD) also known as frontotemporal lobar degeneration (FTLD) is a neuronal atrophy, that results in the loss of brain tissue predominantly from the frontal or temporal lobes, and a loss of spindle neurons. FTD is characterised by personality and behavioural changes, as well as gradual impairment of language skills. Mutations and genetic variants have been identified in the following genes: MAPT -which encodes the Tau protein-, TDP43, FUS/TLS, UPS, VCP, CHMP2B and GRN. Currently, it is estimated that ~15% of FTD patients meet the Amyotrophic lateral sclerosis (herein, ALS) criteria, making FTD and ALS a wide spectrum disease, for which there is no cure or effective treatments.
In this project, we aim to investigate the role of miss-regulation of RNA in the brain and how aberrant transcription can trigger and lead to global and localised neuronal damage. By studying the transcriptional signature of cell-nuclei in various brain regions from postmortem brain tissue from patients and from animal models of the disease, we hope to further understand the underlaying causes of RNA dysregulation and find new clues to advance treatments for patients.
- Single-nuclei RNA-sequencing of frontal cortex and hippocampus of iTDP43 and c9-500 mouse lines.
- Exploring hexanucletiode expansions via CRISPR-Cas9 targeted enrichment and Nanopore sequencing.
- Exploring the role of RNA-binding proteins in the accumulation of toxic RNA in the mouse brain.
Most recent publications:
Simon A. Hardwick, Samuel D. Bassett, Dominik Kaczorowski, James Blackburn, Kirston Barton, Nenad Bartonicek, Shaun L. Carswell, Hagen U. Tilgner, Clement Loy, Glenda Halliday, Tim R. Mercer, Martin A. Smith, John S. Mattick. Targeted, High-Resolution RNA Sequencing of Non-coding Genomic Regions Associated with Neuropsychiatric Functions. Frontiers in Genetics 2019 10:309
- Ling S-C, Polymenidou M, Cleveland Don W: Converging Mechanisms in ALS and FTD: Disrupted RNA and Protein Homeostasis. Neuron 2013, 79(3):416-438.
- Van der Zee J, Van Broeckhoven C: Dementia in 2013: frontotemporal lobar degeneration-building on breakthroughs. Nature reviews Neurology 2014, 10(2):70-72.