Neurodegeneration and Ageing
Neurodegeneration and Ageing
Role of inflammation in neurodegeneration and neurogenesis
Dr. Yvonne Nolan
Aging and neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) are associated with inflammatory changes in the midbrain and hippocampus, respectively. Injury, exposure to environmental toxins or endogenous disease proteins, infection or age may induce prolonged activation of microglia, the resident immune cells of the brain. Consequently, microglial-derived pro-inflammatory cytokines IL-1b and TNFa are thought to be deleterious to the function and survival of neurons. Current research aims to decipher the role of inflammation in (a) degeneration of midbrain dopaminergic neurons pertinent to PD, and in (b) prevention of hippocampal neurogenesis relevant to AD pathology.
Neurotrophic signalling pathways in Parkinson's disease.Dr André Toulouse
Parkinson's disease (PD) is a neurological disease affecting 2% of the population over 65 years of age. It results in severe movement dysfunction, including an inability to initiate movements, slowness of movement and uncontrollable tremors. It is caused by the death of specific brain cells termed dopaminergic neurons. Most therapies aim at controlling the symptoms but cannot prevent or reverse the progression of the disease. A group of proteins called neurotrophic factors has been investigated for their capacity to protect the dopaminergic neurons in PD. While they have been shown to protect the remaining neurons and induce some level of functional recovery, little is know of the mechanisms by which this is achieved. Using cell culture models of PD, we propose to study the pathways within brain cells that are activated or inhibited by these proteins to produce their protective effects. We will also study the effects of combinations of proteins to assess if treatment with multiple proteins offers better protection. Overall, we aim at identifying cellular mechanisms that could be modulated to enhance the protective effects of neurotrophic factors, therefore broadening the scope of possible treatment for PD.
Genetic manipulation of embryonic stem cells for the treatment of neurodegenerative disorders.
A large proportion of neurodegenerative disorders is caused by the loss of a discrete cell population (e.g. dopaminergic neurones in Parkinson's disease). Despite intensive research efforts, symptomatic treatments often have limited efficiency and cannot prevent further degeneration and progression of the disease. Cell replacement strategies are being investigated as a potential therapy where localised populations of cells have degenerated. Sources of such cells have so far included fetal precursors as well as adult and embryonic stem cells. Each of these source populations comes with inherent problems. For example, transplantation of adult stem cells leads to very poor survival and it is not clear whether they represent a true stem cell source or a more committed precursor. On the other hand, the use of fetal material have led to good survival and functional integration but is associated with major ethical issues. In recent years, the interest in using embryonic stem cell lines have attracted strong interest. These cell lines represent theoretically limitless pools of stem cells which can be differentiated in a wide variety of target cell types. It is however difficult to fully differentiate the cells and to maintain the differentiated phenotype in vivo. This results in the appearance of tumours in the transplanted organs and to poor functional recovery. These problems need to be overcome before one can envision an efficient "stem cell therapy". Our current efforts concentrate on identifying genes involved in cell differentiation and maintenance of the differentiated phenotype. We are investigating means of eliminating tumour-forming cells from the transplanted cell population.
Mechanisms of neurodegeneration in CAG trinucleotide repeat expansion disorders
The "polyglutamine disorders" are a group of neurodegenerative disorders caused by the expansion of a coding CAG trinucleotide repeat and include some of the autosomal dominant spinocerebellar ataxias and Huntington's disease. Although the causative proteins are widely expressed, these disorders are characterized by the degeneration of specific neuronal populations. Several hypotheses have been proposed to explain degeneration, including transcriptional impairment, altered protein interactions, direct polyglutamine toxicity and accumulation of toxic protein by-products following the alteration of the protein degradation pathways but no unifying mechanism has emerged yet. We have identified a new mechanism of cell toxicity in these disorders, ribosomal frameshifting resulting in the production of highly toxic polyalanine-containing peptides. Furthermore, we have demonstrated that the toxicity can be modulated by ribosome interacting drugs. Our studies aim at refining these findings and to further study the mechanism by which the ribosome changes its translational frame and its modulation with potential therapeutic agents.
Human genetic disease gene mapping.
Dr Collette Hand
Research focus is the genetic investigation of a variety of conditions and focuses on the mapping and identification of human disease genes through the study of families affected by disease. Linkage analysis remains one of the most robust and reliable methods of identification of disease gene loci. It is independent of gene function or disease pathogenesis and has clearly outlined and developed statistical parameters. The significant advantage of linkage analysis is its application to all type of genetic disease regardless of clinical manifestations. One of the main challenges of this approach is the collection of suitably large families with affected individuals for study. Strong collaborations with clinical colleagues are vital.
Identification of novel genes
Involved in the identification of the causative genes for a number of disorders. Described the gene responsible for a juvenile form of familial amyotrophic lateral sclerosis (ALS) which is a devastating neurodegenerative disorder. Involved in the studies to establish the gene responsible for hidrotic ectodermal dysplasia (HED), an autosomal dominant skin disorder characterised by palmoplantar hyperkeratosis, hair defects (from partial to total alopecia), nail hypoplasia and nail deformities. HED occurs worldwide with a very low frequency, but is more common in French- Canadians and so the known founder effect was exploited to identify the causative gene in this and other populations.
Identification of novel loci
Involved in the identification of novel loci for a number of conditions including congenital hereditary endothelial dystrophy (CHED2) which is a rare corneal disorder, a familial ALS locus (ALS3) and a spastic ataxia locus (SAX1). We have recently identified a novel locus of autosomal dominant restless legs syndrome (RLS) using an Irish family.
Identification of novel mutations
Screening genes for mutations allows the identification of novel mutations which expand the understanding of the disease mechanism and may allow for genotype- phenotype correlations to be developed. This approach has been applied to a number of conditions including familial migraine (ATP1A2 gene), retinitis pigmentosa (RPGR gene), amyotrophic lateral sclerosis (SOD1, ALS2 genes) and hereditary spastic paraparesis (ALS2, PLP, SPG4 genes).
Involved in studies of the genetic basis of pain response in individuals. In the last year we have established new studies on the genetics of the ion channel disorders periodic paralyses and sudden cardiac death through strong clinical collaborations.
Epidemiology and Molecular markers in Gliomas
Dr. Catherine Keohane
Malignant gliomas are the most malignant neoplasm of humans classically associated with a very prognosis. They are increasing in incidence, possibly due to an ageing population and increased survival from other diseases. Glioma behaviour and response to both radiation and chemotherapy is linked to a number of molecular markers, some of which can be reliably tested in formalin fixed paraffin embedded tissue, used routinely in brain tumour diagnosis. Matched with clinical data from our CNS tumour database, this makes them very useful to assess both in archival and recent biopsies of brain tumours.