Centre staff
Professor David Parkinson
Professor of neurobiology
Phone 0114 225 3052
Email d.parkinson@shu.ac.uk
Research interests
Alzheimer's disease
Alzheimer's disease (AD) is the commonest form of dementia affecting the elderly. AD brain pathology is characterized by the presence of senile plaques and neurofibrillary tangles in frontal regions of the brain. The current consensus is that the crucial event in AD pathogenesis is the deposition of the ß-amyloid peptide (A b) after excision from the precursor protein, APP. The site of the generation of A b inside brain cells is unclear; some evidence suggests APP cleavage occurs within the endoplasmic reticulum/intermediate compartment while other studies suggest a post-Golgi location.
The cause of the majority of cases of AD is not known. For some cases, notably the early-onset cases that appear before the age of 50, there is involvement of mutations in one or more of at least three genes. The most common genetic cause of AD is mutations in presenilin 1: over 55 different mutations have been identified. The normal function of presenilins is believed to be g -secretase, though the precise effect of the AD-causing mutations is controversial.
Post-translational processing of APP
Studies are focussed on the cellular events that lead to development of AD by investigating the post-translational processing of APP in normal and stressed cells. In addition, the effect of AD-causing mutations on the cell biology of presenilin and fragments derived from them is being investigated by using transfected cell lines containing a variety of PS1 constructs. Antibody markers to various cell compartments e.g. the ER marker collagen, are being used to identify the intracellular compartments in which the fusion protein resides. The results of these investigations are expected to provide insight into the subcellular compartments involved in APP proteolysis and hence AD pathogenesis.
Proteomics applied to neurodegerative disease
A proteomics approach to neurodegenerative disease pathogenesis is also in progress to explore the hypothesis that the regional susceptibility of different brain regions results from regional differences in the brain proteome. For example, AD affects only frontal lobe and temporal lobe yet, the genetic forms of the altered protein are expressed in all brain areas. Similar observations can be made for Parkinson's disease, Huntington's disease and the strain differences observed for transmissible spongiform encephalopathies. Rodent brain are unsuitable for these studies because neurodegenerative disease susceptibility is demonstrably different from human, so primate brains will be used to undertake a proteomic analysis of brain areas with particular emphasis on comparing those involved in specific neurodegenerative diseases and those that are not.
Recent publications
M.K. Mustafa, A. Nabok, D. Parkinson, I.E. Tothill, F. Salam, A. Tsargorodskaya Detection of B- amyloid peptide (1-16) and amyloid precursor protein (APP770) using Spectroscopic Ellipsometry and QCM techniques: a step forward towards Alzheimers disease diagnostics. Biosensors and Bioelectronics vol 26 1332–1336 (2010)
Newton, J.R.A., D. Parkinson, M.R. Clench (2006) Strategies for examination of Alzheimer's disease amyloid precursor protein isoforms. Anal. Bioanal. Chem. 385: 692-699
Hamacher M, Stephan C, Blüggel M, Chamrad D, Körting G, Martens L, Müller M, Hermjakob H, Parkinson D, Dowsey A, Reidegeld KA, Marcus K, Dunn MJ, Meyer HE and Apweiler R. (2006) The HUPO Brain Proteome Project Jamboree: Centralised summary of the pilot studies. Proteomics 6(6):1719-172.
Stephan C, Reidegeld KA, Hamacher M, van Hall A, Marcus K, Taylor C, Jones P, Muller M, Apweiler R, Martens L, Korting G, Chamrad DC, Thiele H, Bluggel M, Parkinson D, Binz PA, Lyall A. and Meyer HE. (2006) Automated reprocessing pipeline for searching heterogeneous mass spectrometric data of the HUPO Brain Proteome Project pilot phase. Proteomics 6(18):5015-29.
Parkinson D (2003) Inflammation in the pathogenesis of Alzheimer's disease. Inflammopharm. 11: 53.
PhD students
- Mowafag Elazzouzi - Investigation of autophagy in normal and diseased cell systems.
- Natruedee Potiwat - Comparison of the post-translational processing of amyloid precursor protein isoforms
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