Dr Edward Parkin

Lecturer in Biochemistry

Research Interests

Proteolysis in neurodegenerative diseases

Alzheimer's disease (AD) is a neurodegenerative condition caused by accumulation within the brain of neurotoxic amyloid beta (A?)-peptides. These short peptides are derived from the larger amyloid precursor protein (APP) through sequential cleavage by two enzymes known as ?- and ?-secretases. Alternatively, APP can be shed from the cell surface through the action of an ?-secretase which cleaves within the A? region of the molecule thereby precluding the formation of intact A?-peptides.

Creutzfeldt-Jakob disease (CJD) is a neurodegenerative condition which, like AD, is caused by the accumulation of an amyloidogenic protein. In CJD the normal cellular isoform of the prion protein (PrPC) is converted to the more amyloidogenic scrapie isoform (PrPSc). Like APP, PrP is subject to a number of proteolytic cleavages including shedding from the cell surface by an ?-secretase-like activity. A large part of my work involves the characterisation of factors which regulate the proteolysis of PrP and APP.

Proteolysis of angiotensin-converting enzymes

The mammalian angiotensin converting enzyme (ACE) is responsible, inter alia, for the conversion of angiotensin I to angiotensin II and thereby plays a key role in the regulation of blood pressure. Like APP and PrP (above) ACE is subject to proteolytic shedding from the cell surface. My current research interests include the identification and characterisation of the enzyme responsible for ACE shedding and the characterisation of similar shedding events in relation to insect ACE homologues.

ADAM proteases and cancer

A disintegrin and metalloproteases (ADAMs) are zinc-metalloproteases that have been implicated in the shedding of many cell surface proteins including APP and PrP (above). However, key functions for ADAMs have also emerged in relation to the shedding of cell surface ligands involved in cancer progression (e.g. ErbB and Jagged). Therefore, strategies targeting ADAMs might be of relevance in cancer treatments. A developing area of my research focuses upon the identification and regulation of ADAM sheddases involved in cancer development.

Proteolysis in Trypanosomal disease

The African Trypanosome is transmitted by tsetse flies and causes African sleeping sickness. In the bloodstream of its host the trypanosome evades the immune system by undergoing antigenic variation through periodic switching of its predominant surface protein, the variant surface glycoprotein (VSG). VSG is proteolytically cleaved from the membrane surface through the action of major surface protease A (MSP -A). Some of my current research focuses on the development of MSP-A inhibitors with a view to preventing VSG shedding and, ultimately, evasion of the body's immune system by the trypanosome.