Understanding the molecular mechanisms underpinning neurodegenerative diseases represents the major neuropathology research theme
Neurodegenerative diseases are progressive conditions with poor prognoses and often with limited diagnostics and treatment options. The pathological mechanisms underlying neurodegenerative diseases and their progression are widely debated and likely involve many diverse pathways, such as protein misfolding and aggregation, excitotoxicity, oxidative damage, mitochondrial dysfunction and inflammation.
The focus of our research in Edinburgh is amyotrophic lateral sclerosis (ALS), which is a neurodegenerative disease characterized by the selective degeneration of motor neurons. Protein misfolding is thought to be a key pathway in the pathogenesis of ALS as the pathological misfolding, aggregation and cytoplasmic accumulation of a protein called TDP-43 is the unifying feature seen at post-mortem in the brains of the majority of cases of ALS.
Here in Edinburgh neuropathology we have access to a dedicated ALS brain bank, with high quality, deeply-phenotyped post-mortem central nervous system (CNS) tissue from a diverse cohort of ALS patients with both genetic and sporadic aetiologies. Our research focuses on the implementation of cutting-edge molecular pathology techniques to probe disease mechanisms to ultimately inform both drug discovery and biomarker development in the field.
Most recently, these techniques have included spatial transcriptomics (1) and BaseScope (2), allowing us to probe disease-related transcriptional dysregulation, whilst preserving spatial, cell-type specific, single-cell resolution. Moreover, the deeply-phenotyped nature of our cohort of CNS tissue, including standardized cognitive phenotyping, whole genome sequencing and linked-medical records, continues to reveal ever-more insightful clinico-pathological correlations.
Furthermore, we have a close collaborative relationship with research groups within the Euan MacDonald Centre for Motor Neurone Disease Research. The bilateral nature of this relationship allows us to investigate hypotheses generated from our human post-mortem studies in model systems, and provides our colleagues with the opportunity to validate findings from their model systems in relevant, deeply-phenotyped, human post-mortem tissue (see an example of a recent collaborative project in reference 3).
- Ståhl PL, Salmén F, Vickovic S, Lundmark A, Navarro JF, Magnusson J, et al. Visualisation Visualisation and analysis of gene expression in tissue sections by spatial transcriptomics. Science. 2016 Jul 1;353(6294):78-82
- Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A, et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn. 2012 Jan;14(1):22-9.
- Selvaraj BT, Livesey MR, Zhao C, Gregory JM, James OT, Cleary EM, Chouhan AK, Gane AB, Perkins EM, Dando O, Lillico SG, Lee YB, Nishimura AL, Poreci U, Thankamony S, Pray M, Vasistha NA, Magnani D, Borooah S, Burr K, Story D, McCampbell A, Shaw CE, Kind PC, Aitman TJ, Whitelaw CBA, Wilmut I, Smith C, Miles GB, Hardingham GE, Wyllie DJA, Chandran S. 2018. C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity. Nat Commun. 24;9(1):347.