Fellows Lecture in Pairs: 'Neuroproteomic approaches to identifying novel mechanisms of cognitive resilience in neurodegeneration’ and ‘Using high-throughput biology approaches to understand mitochondrial dysfunction in Parkinson’s’
Dr Becky Carlyle: ‘Neuroproteomic approaches to identifying novel mechanisms of cognitive resilience in neurodegeneration’

The most common form of dementia, Alzheimer’s Disease (AD), likely arises as a combination of genetic risk, lifetime stressors and disease comorbidities, leading to dysregulation in neuronal signaling, synapse loss, insoluble protein deposition, and ultimately, neuron death. For many years cases of Alzheimer’s Disease have been confirmed post-mortem by the presence of amyloid beta plaques and neurofibrillary tau tangles in characteristic brain regions. Population-based studies have repeatedly shown that there are a large proportion of resilient individuals who harbour high levels of AD pathology but experience no cognitive impairment. This phenomenon of resilience is poorly understood but represents a clear opportunity for therapeutic development.

In this talk Dr Carlyle will discuss some of her current projects which use neuroproteomics to identify novel mechanisms of cognitive resilience from post-mortem brain tissue and cerebrospinal fluid. She will discuss highlights from three projects; the analysis of enriched organellar fractions from post-mortem brain tissue, mapping and identifying endogenously cleaved neuropeptides associated with cognition, and the identification of two metabolic proteins, PKM and ALDOA, as potential markers of Alzheimer’s Disease in cerebrospinal fluid.

Dr Brent Ryan: ‘Using high-throughput biology approaches to understand mitochondrial dysfunction in Parkinson’s’

Parkinson’s disease (PD) is characterized by mitochondrial dysfunction in both the periphery as well as in the dopaminergic neurons of the midbrain which are lost during disease progression. Mutations in a number of genes including the mitophagy-regulating genes PINK1 and PRKN (Parkin) have been shown to cause PD. In addition, mutations in other genes encoding α-synuclein and LRRK2 have been linked with mitochondrial roles.

We have assessed mitochondrial function and mitophagy in primary neuronal cultures and patient iPSC-derived dopaminergic neurons, observing consistent mitochondrial dysfunction across models. In addition, unbiased approaches including post-translational proteomics of these models also identify mitochondrial dysfunction as a key cellular phenotypes in these models.

We have developed a CRISPRi platform to phenocopy patient mutations and dissect gene function in iPSC-derived neurons. We have used sgRNA targeting PINK1 and PRKN in dCas9-KRAB expressing iPSC lines and assessed the effect of knockdown on mitochondrial function and PINK1-dependent mitophagy.

We are now aligning these approaches to use CRISPRi to interrogate pathways at scale and perform functional genomics in human iPSC-derived neurons to understand the biology of Parkinson’s and identify novel therapeutics.
Date: 3 February 2023, 13:00 (Friday, 3rd week, Hilary 2023)
Venue: Sherrington Library, off Parks Road OX1 3PT
Speakers: Dr Becky Carlyle, ARUK Coordinator (University of Oxford), Dr Brent Ryan (University of Oxford )
Organising department: Department of Physiology, Anatomy and Genetics (DPAG)
Organisers: Dr Mootaz Salman (DPAG, University of Oxford), Dr Armin Lak (DPAG, University of Oxford)
Organiser contact email address: hod-pa@dpag.ox.ac.uk
Host: Professor David Paterson (DPAG, University of Oxford)
Part of: DPAG Head of Department Seminar Series
Booking required?: Not required
Audience: Members of the University only
Editor: Talitha Smith