Small areas of bleeding in the brain, known as cerebral microbleeds (CMB), are emerging as important features of an aging brain. Not only are they a marker for unhealthy blood vessels associated with development of dementia, but they also indicate an increased risk of major bleeding in the brain. This is particularly a concern in the common situation where doctors need to use medicines that stop clots from forming, and therefore increase risk of bleeding, to prevent heart attacks and ischaemic strokes. Although CMB are common they are not checked for routinely in conventional commonly us
The aim of this PhD proposal is to develop novel machine learning algorithms (e.g., deep learning) to predict the risk of dementia in Type 2 diabetes, and detect early signs of such disease with association of clinical and genomic data in clinical settings. There are strong links between Type 2 Diabetes (T2D) and dementia. With increasing numbers of people developing T2D, detecting early signs of dementia is important to better understand how it can be delayed or prevented.
Supervisors: (Lead): Dr Ian Morrison, Department of Neurology, Ninewells Hospital, Professor Emanuele Trucco, School of Science and Engineering, Professor Stephen McKenna, School of Science and Engineering.
Degrading proteins in a timely manner to dispose of misfolded and damaged proteins is essential for a healthy cell. In ageing cells and organisms, there is a deterioration in the ability of cells to clear proteins resulting in the accumulation of misfolded proteins. Deposition of misfolded protein aggregates is a hallmark of many neurodegenerative diseases. It is not understood why quality control systems and the degradation capacity of a cell decline with age.
Nerve cells in the brain are interconnected within complex networks and synaptic communication within these brain networks determines how we think and behave. In neurodegenerative disorders like Alzheimer’s disease (AD), synaptic communication within brain networks are impaired leading to significant memory deficits and dementia. Clinical studies indicate that diet and lifestyle are key risk factors for AD. Indeed, metabolic imbalance is an important contributory factor in AD and recent evidence has linked the hormone leptin to an increased incidence of AD.
Parkinson’s disease (PD) is a leading cause of neurodegeneration in man. Mutations in the PINK1 kinase lead to autosomal recessive PD. Previous research in our lab has defined a cell signalling pathway for PINK1. Under basal conditions PINK1 is inactive however upon exposure to mitochondrial uncouplers that induce mitochondrial depolarization, PINK1 becomes stabilized and activated. Upon activation PINK1 phosphorylates a Parkinson’s disease-linked ubiquitin ligase, Parkin and ubiquitin.
According to the WHO, depression is now the leading cause of poor health and disability worldwide. Currently available drugs have limited and variable efficacy, and typically take weeks to improve mood and behaviour. The problem stems, in part, from our lack of understanding of the brain mechanisms underlying depression, and uncertainty surrounding the ways in which antidepressants work. Although drug-discovery efforts have typically focussed on the actions of neuromodulators such as serotonin (e.g.
The transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is the master regulator of the cellular cytoprotective responses, controlling the expression of nearly 2% of the human genome. The Nrf2 regulatory network is at the interface between redox and intermediary metabolism (Hayes and Dinkova-Kostova, 2014), and plays a critical role in the resolution of inflammation (Mills et al. 2018).
Protein O-GlcNAcylation is a post-translational modification that is emerging as being neuroprotective by “shielding” proteins involved in neurodegenerative proteinopathies (e.g. ). The van Aalten lab is studying the biological and molecular mechanisms underpinning this modification using a combination of biochemistry, structural biology and mouse/Drosophila genetics [2,3,4]. Neurodegenerative diseases are increasingly recognised as not necessarily neuronal cell autonomous .
Mutations in the NEK1 kinase have recently been identified in patients with familial motor neurone disease (MND). NEK1 encodes a kinase of 1258 amino acids and previous studies have linked NEK1 activity to regulation of DNA repair pathways. How defects in DNA repair lead to MND is currently unknown. The project involves cutting-edge technologies carried out in a world-class institution to characterize the function of NEK1 in relevant neuronal systems. The project will also determine how mutations lead to MND, and analyse the impact of these mutations on cell responses to DNA damage.