Dr
Kirsty McMillanProfile page
Tenure-Track Fellow
Biochemistry, Cell and Systems Biology
- Tenure-Track FellowBiochemistry, Cell and Systems Biology
ABOUT
Personal Statement
In August 2024, I set up my independent lab at the University of Liverpool as a Tenure-Track Fellow investigating the role of the endosomal system in health and neurodegenerative disease.
Throughout my career, my aspiration has been to understand the biological pathways affected in neurodegenerative conditions. I have developed a wide breadth of expertise across a range of disciplines including biochemistry, neuroscience, and pharmacology, and developed an array of methodologies to understand the molecular mechanisms driving these conditions. During my undergraduate degree, I saw the need for better animal models that more accurately reflected Parkinson’s pathology which motivated my PhD studying the role of microRNAs in the regulation of alpha-synuclein in Professor Maeve Caldwell's lab (University of Bristol). For my postdoctoral work, I wanted to further understand the subcellular processes underlying neurodegeneration and so moved my research into protein biochemistry in Professor Peter Cullen’s lab (University of Bristol). Here, I was instrumental in driving forward a new avenue of exploration into the role of the endosomal system in neurodegenerative disorders, developing key methodologies, including quantitative proteomics, in primary neuronal and glial cultures, and establishing key collaborations across multiple fields, including structural biology and electrophysiology. Through my work, I have identified the mis-trafficking of integral proteins, due to endosomal dysfunction, as a key mechanism driving neurodegeneration. I have been recognised in the neurodegenerative and membrane trafficking fields through invitations to present my research at several conferences, chair live discussions and review papers.
Research Overview
Research Interests
Neurodegenerative diseases including Alzheimer's disease and Parkinson's disease are a global public health priority, affecting millions of people worldwide. We are in urgent need of early-stage diagnostic markers and new therapeutic targets to treat these diseases. My lab aims to meet these needs through understanding the potential role of the endosomal system in neurodegenerative pathology.
The Endosomal System
The endosomal system comprises an inter-connected series of intracellular membrane-bound compartments controlling protein and lipid transport. Perturbation of the endosomal system has been implicated in the initiation and progression of several neurodegenerative disorders with neuronal endosomal swelling classed as an early hallmark of disease. Retromer is an endosomal trimeric complex important for regulating the retrieval and trafficking of numerous proteins away from the degradative pathway. Retromer expression is significantly decreased in Alzheimer's patients, and mutations have been found in Parkinson's patients. Retromer associates with sorting nexin-27 (SNX27) when trafficking specific proteins to the cell surface, critical for cells communicating with their extracellular environment. SNX27 dysfunction has been implicated in Down’s syndrome, which greatly increases the risk for developing Alzheimer's disease. We are interested in exploring the endosomal system and SNX27-Retromer in different cell types of the brain including neurons and astrocytes to understand how perturbation of this system can lead to disease. We use a range of techniques including cell biology, quantitative proteomics and biochemistry.
Interplay between Astrocytes and Neurons
Crucially, the role of the endosomal system in glial cells is unclear and understudied, leaving a critical gap in our knowledge. Astrocytes, a form of glial cells, are known to play an essential role in neuronal health and have been heavily implicated in neurodegenerative pathology. We are focused on understanding the role of the astrocytic endosomal system in astrocyte function, neuronal health and ultimately, neurodegenerative disease.