... understanding life in molecular detail

Dr James Duce

Neurobiology, Metallomics, Neurodegenerative disease, Iron homeostasis.

By recently providing a novel candidate function we now begin to explain APP’s diverse trophic and morphoregulatory activities and elucidate the vulnerability of the body to age-associated iron accumulation. Our continued research in this area will not only strengthen a mechanism for iron regulation in general neurobiology but also explain how iron accumulation may exacerbate age-related neuropathological disease. Restoring or replacing APP’s function may lead to the future development of new therapeutics and predictive biomarkers for the iron accumulative conditions present in neurodegenerative diseases such as AD and PD.

Current major projects include:
  • The physiological role of ß-amyloid precursor protein
  • High valent metal homeostasis in neurodegenerative disease
  • Metal related disease-modifying treatments for neurological disorders

Dr Duce is a Principal Researcher and Neuroscience Lecturer in the School of BioMedical Sciences at the University of Leeds and is an associate member of the Astbury Centre. James obtained his PhD in neurobiology at the University of Wales College of Medicine in 2002, and immediately transitioned abroad to built his international experience by working as a research associate at Boston University School of Medicine with Prof. Carmela Abraham before moving to Australia and working with Profs. Ashley Bush and Colin Masters. After more than 10 years working overseas in some of the most recognized international groups, James returned to the UK and joined the University of Leeds at the beginning of 2012.

Research Overview:

  • Advancing the basic understanding of β-amyloid precursor protein’s role in neuroprotection.

β-amyloid precursor protein is an established copper and zinc binding protein ubiquitously expressed as a full-length type 1 transmembrane protein, and processed into fragments, including the soluble species found in plasma (sAPP) and toxic β-amyloid peptide that accumulates in the ageing brain as well as neurodegenerative diseases including Alzheimer’s disease. Known to have neurotrophic properties, APP function was until recently largely unknown. But with a regulation of APP expression by iron regulatory protein (IRP) implying an interaction with iron status, our group has recently strengthened an iron relationship through the discovery of a conserved iron binding motif in the ectodomain, similar to that present in ferritin and other iron transporting proteins, and APP’s requirement for iron regulation in cells such as neurons. APP’s ability to regulate iron is through its interaction with the iron exporter ferroportin and its ability to facilitate the removal of cytoplasmic iron via ferroportin’s translocation to the cell surface (see Figure). This is similar to another protein called ceruloplasmin that is not found in neurons. Both APP and CP are able to prevent cellular oxidative stress caused by Fenton and Haber-Weiss chemistry and loss or mislocalization of either protein may in part be responsible for pathological Fe2+ accumulation in neurodegenerative diseases. Aceruloplasminemia patients carry a mutation in ceruloplasmin (CP) that leads to primarily glial iron accumulation that in turn causes neuronal loss and dementia while we have recently discovered that loss of functional APP may have a similar detrimental consequence to iron build up in Alzheimer’s disease.

Additional data by our group also indicates that APP is a significant factor in the clearance of catecholamine. It is notable that both APP and CP possess this ability as well as regulating iron homeostasis even though this is through independent processes as their domains that are not structurally homologous. This is unlikely to be coincidental and we are currently investigating whether they have evolved to meet a similar physiological need in differing chemical environments. The modulation of catecholamine levels in the brain is an important end-effect for several major classes of psychotropic drugs. The discovery that APP may influence catecholamine levels at these sites has important implications for clinical pharmacology.

  • Iron homeostasis in neurodegenerative disease.

Iron is essential for the normal function of the body as its ability to freely receive and donate electrons is critical for many metabolic processes including oxidative phosphorylation, nitric oxide metabolism, oxygen transport and neurotransmitter production. A deficiency in iron can lead to metabolic stress on these processes. But when this metal is at an increased presence and not correctly guarded it can be converted to a potentially harmful product that leads to an increased susceptibility to oxidative stress. The balance between disposing of and retaining iron is fundamental for keeping a healthy cell. While much work over the years has been done to investigate the homeostasis of iron throughout the body, very little is known as to how iron is regulated within the different cell types of the brain. In particular how each cell type is able to independently regulate this metal but also assist neighbouring cells of a different type with their transport of iron. The ageing brain is particularly vulnerable to cellular iron dysregulation as are patients with a broad range of brain disorders, including Alzheimer’s and Parkinson’s disease and a better understanding is required as to how this occurs. While our research focuses on APP, the group also investigates the role all iron regulatory proteins play in the brain’s cellular import, storage and export under conditions that simulate neurodegenerative disease and their involvement in the oxidative damage commonly observed in neurodegenerative disease.

  • Investigating metal related disease-modifying treatments for relevant neurological disorders.

Metal dyshomeostasis and oxidative damage are common features of neurodegenerative diseases such as Parkinson’s, Alzheimer's and Huntington's disease. It was originally believed that general removal of metals from tissue by ‘chelation’ was the best course of action in these diseases. However, as was explained earlier, metal homeostasis in the brain is paramount for a healthy cell and deficiency in cellular metals can often be just as detrimental as accumulation. It is for this reason that recent extensive work on the neuroprotective mechanism of metal attenuating compounds now suggests a more subtle mechanism of action whereby they restore brain biometals to their correct anatomical compartments via an ability to perform as transition metal ionophores or "chaperones". A central aim of our research has been to identify metal attenuating compounds that can mitigate ongoing neuronal loss after the cell death cascade has already commenced. However, while these compounds were effective in preventing neuronal injury when administered before neurodegeneration, it was significantly less effective when administered after initiation of the lesion. We are therefore currently heavily involved in searching for more effective molecules that are suitably neuroprotective even when administered after disease onset.


Detailed research programme                  Close ▲

Selected Publications

  1. Gunn AP, Wong BX, Johanssen T, Griffith J, Masters CL, Bush AI, Barnham KJ, Duce JA*, Cherny RA*. (2016) ‘Amyloid-Beta Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization and Calcium-Influx in Neurons’. J Biol Chem. 291(12):6134-45.

  2. Wong BX, Tsatsanis A, Lim LQ, Adlard PA, Bush AI, Duce JA. (2014) “β-Amyloid Precursor Protein Does Not Possess Ferroxidase Activity but Does Stabilize the Cell Surface Ferrous Iron Exporter Ferroportin”. PLoS One. 9(12):e114174. doi: 10.1371/journal.pone.0114174.

  3. Duce JA, Ayton S, Miller AA, Tsatsanis A, Lam LQ, Leone L, Corbin JE, Butzkueven H, Kilpatrick TJ, Rogers JT, Barnham KJ, Finkelstein DI, Bush AI. (2013) “Amine oxidase activity of β-amyloid precursor protein modulates systemic and local catecholamine levels.” Mol Psych.18(2):245-54.

  4. Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, Wong BX, Adlard PA, Cherny RA, Lam LQ, Roberts BR, Volitakis I, Egan GF, McLean CA, Cappai R, Duce JA, Bush AI. (2012) “Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export.” Nat Med. 18(2):291-95