Piers Emson
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• Recent, selected Publications

Molecular mechanisms underlying neurodegenerative disease

The targets of our research are Parkinson’s disease and Alzheimer’s disease. These are both neurodegenerative diseases which, in their sporadic forms typically occur in old age, in general after 50 years, and with increasing incidence beyond this decade.

Figure 1 (Click to enlarge)
Parkinson’s disease leads to specific cell loss.
The substantia nigra (black substance) area (SNc)
is damaged with loss of specific cells as indicated by the
changes between these pictures. Loss of dopamine
leads to difficulty initiating movement and tremor
characteristics of Parkinson’s disease.

Both Alzheimer’s and Parkinson’s disease are characterised by intra-neuronal accumulation of proteins, which may contribute to, or cause the specific cell death characteristic of these conditions. In the case of Parkinson’s disease the pathological hallmark of this condition - the Lewy body - contains a protein named -synuclein. In rare cases of familial Parkinson’s disease mutations in this protein give rise to the condition. In Alzheimer’s disease the cerebral cortex and hippocampus are characterised by plaques which are enriched in a protein termed β-amyloid and intra-neuronal tangles enriched in a microtubule associated protein termed, tau. Again mutations in the β amyloid precursor (APP) or in the Tau protein predispose affected individuals to disease.

In both diseases mishandling of proteins causes accumulation of tangled or filamentous protein and neurodegeneration. In order to understand these conditions further we have looked in detail at the pathology of these conditions using human post-mortem brain tissue (see Figures) and are using techniques of gene and protein profiling (together with Dr Mike Starkey and colleagues in the MRC HGMP at Hinxton) to explore further the mechanisms (changes in gene or protein expression) underlying the development of the sporadic forms of Parkinson’s disease and Alzheimer’s disease.

Figure 2 (Click to enlarge)
A. Localisation of the microtubule associated protein tau , a major component of the characteristic tangles of Alzheimer’s disease in the hippocampus of a patient who died with a diagnosis of Alzheimer’s disease.

B. Localisation of immunoreactivity for ‘Huntingtin’ the protein associated with the Huntington disease gene in the human cerebral cortex.

C. Localisation of transcription factor immunoreactivity (ATF2 –red) with tau-green in the hippocampus.

D. Localisation of Jnk immunorecativity (red) with β-amyloid (green) in the hippocampus.

The aim of this work is to identify novel genes that may be causal and may represent novel targets for therapeutic intervention. A particular focus is the study of signalling pathways in neurodegenerative disease where pathways such as the mitogen activated protein kinase cascade (MAPK) may be activated.

Recent, selected publications

Caudle WM, Richardson JR, Wang MZ, Taylor TN, Guillot TS, McCormack AL, Colebrooke RE, Di Monte DA, Emson PC, Miller GW (2007) Reduced vesicular storage of dopamine causes progressive nigrostriatal neurodegeneration.
Journal of Neuroscience 27 8138-8148
http://dx.doi.org/10.1523/JNEUROSCI.0319-07.2007

Emson PC (2007) GABAB receptors: structure and function.
Progress in Brain Research 160 43-57
http://dx.doi.org/10.1016/S0079-6123(06)60004-6

Higashi S, Moore DJ, Colebrooke RE, Biskup S, Dawson VL, Arai H, Dawson TM, Emson PC (2007) Expression and localization of Parkinson's disease-associated leucine-rich repeat kinase 2 in the mouse brain.
Journal of Neurochemistry 100 368-381
http://dx.doi.org/10.1111/j.1471-4159.2006.04246.x

Lambourne SL, Humby T, Isles AR, Emson PC, Spillantini MG, Wilkinson LS (2007) Impairments in impulse control in mice transgenic for the human FTPD-17 tauV337M mutation are exacerbated by age.
Human Molecular Genetics 16 1708-1719
http://dx.doi.org/10.1093/hmg/ddm119

Biskup S, Moore DJ, Celsi F, Higashi S, West AB, Andrabi SA, Kurkinen K, Yu S-W, Savitt JM, Waldvogel HJ, Faull RLM, Emson PC, Torp R, Ottersen OP, Dawson TM, Dawson VL (2006) Localization of LRRK2 to membranous and vesicular structures in mammalian brain.
Annals of Neurology 60 557-569
http://dx.doi.org/10.1002/ana.21019

Colebrooke R, Humby T, Lynch PJ, McGowan DP, Xia J, Emson PC (2006) Age-related decline in striatal dopamine content and motor performance occurs in the absence of nigral cell loss in a genetic mouse model of Parkinson's disease.
European Journal of Neuroscience 24 2622-2630
http://dx.doi.org/10.1111/j.1460-9568.2006.05143.x