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| DNA investigation in Neurodegenerative disorders |
| Catarina Oliveira (CNC); Manuela Grazina (CNC) |
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Neurodegenerative disorders are complex disorders and the mechanisms underlying the phenotypic expression of this group of diseases are not clearly understood. Finding genetic risk factors, either from nuclear or mitochondrial genome origin, will contribute to identify new tools for early diagnosis, as well as to support the development of more rationale therapies, including the implementation of pharmacogenetic approach.
We have continued the mtDNA screening analysis in Alzheimer’s disease (AD) and Frontotemporal dementia (FTD) patients and age matched controls. Evidences that mtDNA mutations/ polymorphisms may contribute to the risk of disease expression, coul be demonstrated. The evaluation of mtDNA ND1 sequence variations in a larger sample of FTD patients started to be performed, following the evidences of the involvement of MRC complex I in FTD, reported in 2004 (Grazina M, Silva F, Santana I, Santiago B, Oliveira M, Cunha L, Oliveira C. Frontotemporal dementia and mitochondrial DNA transitions. Neurobiol. Dis. 2004; 15-2: 306-311).
A strategy to improve the study of the mtDNA haplogroups, to be applied in the investigation of neurodegenerative disorders, including AD and FTD was set up. The phylogenetic resolution was improved and 10 new haplogroups are now available for analysis. The frequency of 27 mtDNA haplogroups in 358 patients (mean age 71.2 years) and 230 age matched controls (mean age 64.3 years), was evaluated. So far, no relevant differences were detected, considering individual haplogroups. The grouping analyses will be performed in order to increase the statistical probability of finding significant differences in the frequency distribution.
A collaboration project with the Centre for Hereditary Eye Diseases, Department of Ophthalmology, University Hospital of Coimbra, and Visual Neuroscience Laboratory, Faculty of Medicine of Coimbra, has been initiated, in order to set up the genome screening and evaluate the involvement of mtDNA sequence variations and MRC activity in eye diseases.
RNA analysis for the investigation of genetic expression variations is being performed.
During the last year we have continued to focus on the nuclear genetic factors known to underlie the process of neurodegeneration, mainly in Alzheimer’s (AD) and Parkinson’s (PD) diseases. Given the socio-economic impact of neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease, it is important to design a viable strategy for the delineation of genetic predisposition in complex traits. We are tackling this problem from different perspectives: first, by studying rare familial forms of disease and then extrapolating the function of genes involved to related conditions – for this purpose, we are continuing to collect samples from individuals with positive familial history who do not present a clear genetic cause to their condition; second, identifying common genetic variability that confers risk for disease – in order to accomplish this, we are collecting as many samples from idiopathic forms of these diseases as possible, in collaboration with the Movement Disorders and Dementia Clinics nation-wide. Additionally, we have collected control samples for a series representative of the elderly Portuguese population – 400 samples from healthy individuals (mean age 67,9 years) were collected, which will allow to obtain a clear view of the genetic variability present in the Portuguese population. |
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| PUBLICATIONS |
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| Grazina M, Pratas J, Silva F, Oliveira S, Santana I, Oliveira C (2006). Genetic basis of Alzheimer’s dementia. Genes, Brain and Behaviour 5(2), 92–107. Review. |
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| Guerreiro RJ, Bras JM, Santana I, Januario C, Santiago B, Morgadinho AS, Ribeiro MH, Hardy J, Singleton A, Oliveira C. (2006) Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a Portuguese cohort. BMC Neurol. 6:24. |
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