Dr Zoe Holloway

Research

zoeI have been involved in two projects for the Monaco group, both focused on the function of genes identified by the group to be linked with Menkes Disease or developmental dyslexia.

Menkes Disease

The first project I worked on aimed to characterise the copper transporter ATP7A, which is mutated in patients with Menkes disease.

Copper is an essential trace element, being an important co-factor for many enzymes involved in processes such as neuronal function and embryonic development. Excess copper is toxic to cells so tight regulation is vital. Amongst the proteins known to be important in copper homeostasis are the copper transporting P-type ATPases ATP7A (Menkes protein, MNK) and ATP7B (Wilson protein, WND).    

The importance of copper transport in human development is underscored by studies linking mutations in the genes ATP7A and ATP7B with the clinical pathologies observed in Menkes and Wilson diseases, respectively. Menkes disease is a fatal X-linked disorder that leads to death in early childhood, caused in part by neurological degeneration. The disease results from systemic copper deficiency caused by the failure of ATP7A to translocate copper from the small intestine into the circulation for delivery to the rest of the body. Inactivating mutations in ATP7B, observed in Wilson disease, prevent biliary excretion of the metal and cause copper accumulation (and subsequent damage) in the liver.

Within the cell the copper transporters reside predominantly in the in the trans-Golgi network, where they are thought to supply copper as a co-factor for cuproenzymes traversing the secretory pathway.  

Both transporters sense and respond to intracellular copper levels by relocating to sites where copper transport is needed. When intracellular copper levels increase the transporters re-localise to the relevant membrane (apical or basolateral), or vesicles near to the membrane, to eliminate excess copper from the cell. Our goal is to understand the novel mechanisms that MNK and WND exploit to traffic within the cell in response to copper.

Developmental Dyslexia

More recently I have been part of the team investigating the function of the protein KIAA0319, which has been linked to Developmental Dyslexia. Little is known about the function of KIAA0319 and we aim to characterise this in mammalian model systems. 

I am also a STEM Ambassador ( www.stemnet.org.uk/content/ambassadors) which involves my participation in public engagement activities such as Science in the kitchen/Oxfordshire Science festival or science demonstrations to school groups here at the WTCHG.

Publications