Dr Angeleen Fleming
- Group Leader
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About
Our lab investigates the regulation of intracellular protein clearance pathways—principally the ubiquitin–proteasome and autophagy–lysosome systems—as well as unconventional protein secretion. We focus on how these processes contribute to maintaining lifelong health of the nervous system.
Protein clearance pathways are essential for neuronal function across the lifespan. They regulate neurogenesis, support synaptic plasticity, and continuously remove misfolded or aggregation-prone proteins, thereby protecting against the development of late-onset neurodegenerative diseases. In parallel, unconventional protein secretion has emerged as both a non-canonical secretory route and an important mechanism for intercellular communication within the central nervous system.
Angeleen Fleming obtained her degree from UCL and PhD from Great Ormond Street Institute of Child Health and has worked in both academia and biotech. She has ~20 years’ experience of working with zebrafish as a model organism and has run a zebrafish research group at the University of Cambridge since 2009. Work in the Fleming lab has two main focuses: firstly, developing and using zebrafish transgenic models of neurodegenerative disease to understand the causes of neurodegeneration and to investigate therapeutic mechanisms and secondly, to elucidate the role of autophagy and other protein clearance pathways in vivo in normal physiology and in pathological conditions.
Research
We use complementary cell-based systems and zebrafish models to study both childhood and late-onset neurological disorders, with a particular focus on the role of protein clearance pathways in disease pathogenesis.
Neurodegenerative diseases
Many late-onset neurodegenerative diseases (NDs) are characterised by intracellular protein misfolding and aggregation and are collectively referred to as proteinopathies. These include Alzheimer’s disease, Parkinson’s disease, tauopathies, and Huntington’s disease.
Despite their prevalence, there are currently no therapies that effectively halt or prevent neurodegeneration in humans. As life expectancy increases, the societal and economic burden of these diseases is expected to grow substantially. Our research aims to define how aggregate-prone proteins drive disease pathology and to identify cellular pathways that can enhance their clearance and offer potential therapeutic strategies.
Neurodevelopmental disorders
Neurodevelopmental disorders impose a profound burden on affected individuals and their families, yet for many conditions the underlying biology remains poorly understood and targeted treatments are lacking.
A growing body of evidence implicates disrupted protein clearance—particularly defects in autophagy—in impaired brain development. These defects can lead to clinical features such as microcephaly, developmental delay, dysmorphism, and intellectual disability. We develop and study model systems for a range of neurodevelopmental disorders to uncover their cellular mechanisms and to explore potential therapeutic approaches.
Extracellular vesicle–mediated protein clearance and signalling
Unconventional protein secretion occurs via multiple pathways, and our lab is particularly interested in the mechanisms that regulate the selective loading of proteins into transport vesicles for secretion. These extracellular vesicles (EVs) can be taken up by neighbouring cells, enabling direct cell-to-cell communication through the transfer of protein cargo.
In the context of neuronal health, we investigate how EV-mediated signalling between neurons and glial cells contributes to maintaining CNS health and changes during ageing.
In neurodegenerative disease, EV-mediated secretion may play dual and potentially opposing roles. On one hand, it may facilitate the removal of misfolded or aggregation-prone proteins from neurons, with subsequent uptake and clearance by astrocytes or microglia. On the other hand, it may contribute to the propagation of pathological proteins between cells, promoting the spread and seeding of aggregates across neural networks.
Professor David Rubinsztein – Cambridge Institute for Medical Research
Professor Maurizio Renna - University of Naples Federico II
Dr Lars Schlotawa - University Medical Center Göttingen
Dr Christopher Wilkinson – Royal Holloway, University of London