instituto de biologia molecular e celular | institute for molecular and cell biology
Previous research results:
Our group focuses on genetics of neurological diseases, mainly the spinocerebellar ataxias (SCAs), Huntington disease and other movement disorders.
We have been involved in the identification and characterization of genes and mutations for dominant (SCA) and recessive hereditary ataxias (AOA), Huntington disease (HD) and HD-like disorders and hereditary spastic paraplegia (HSP/SPG).
We have also been interested in complex disorders, particularly in the study of migraine (familial and association studies), to assess familial aggregation and ascertain susceptibility genes. We have also studied paediatric stroke, multiple sclerosis and hypodontia.
Our animal-based research (mice and C. elegans) has been centred on Friedreich ataxia, Machado-Joseph disease (MJD/SCA3) and SCA6, to evaluate disease mechanisms as well as the function of proteins involved. Cell models have been used to characterize ataxin-3 interactors and assess the role of protein processing and protein degradation systems in neurodegenerative disorders.
We have been also involved in the identification of disease modifiers and epigenetic modification in HD, MJD and familial amyloid polyneuropathy (FAP) ATTRV30M.
Another interest has been the study of founder effects, ancestral haplotypes and mutational origins mainly in MJD, but also SCA2 and SCA10.
Our unit is served by a large multidisciplinary team, including clinical neurology and epidemiological studies, psychosocial genetics and ethics; population genetics, genetic epidemiology and historical genetics; gene mapping and mutational analysis, functional genomics and animal models.
IMAGE: This image shows a C. elegans worm, an excellent model to study neurodegenerative diseases. Our interests start with the clinical characterization of patients and families, using genetic epidemiological tools and the identification of mutations and mechanisms responsible for disease, and continue up to the functional characterization of normal and mutant proteins, but also population studies and evolution. Our group has large experience with the use of human patients, and animal and cell-based models.
Future research goals:
Identification of new genes and mutations in neurodegenerative disorders are still one of our major goals, as these can be translated into regular clinical practice and have a direct impact in patient management and genetic counselling in their families.
We will continue the search for cell pathways and pathogenic mechanisms in neurodegeneration, through the study of cell and animal models. We are particularly interested on the impact of mutations in protein folding and aggregation, as well as on toxic intermediate species and the role of protein degradation systems in aggregate formation and clearance.
We will further invest on the search for disease modifiers (genetic, epigenetic and environmental), through human, cell and animal-based approaches that might help clarifying the disease mechanisms contributing to Huntington, SCAs, FAP ATTRV30M or Parkinson disease.
Patient studies and genetic epidemiological tools will be used also for identification of modifiers. In addition, understanding the genetic contribution to the aetiology of complex diseases will remain one of our aims.
Emmel VE, Alonso I, Jardim LB, Saraiva-Pereira ML, Sequeiros J (2011): Does DNA methylation in the promoter region of the ATXN3 gene modify age at onset in MJD (SCA3) patients? Clin Genet 79:100-2
Sequeiros J, Ramos EM, Cerqueira J, Costa M do C, Sousa A, Pinto-Basto J, Alonso J (2010): Large normal and reduced-penetrance alleles in Huntington disease: instability in families and frequency at the lab, at the clinic and in the population. Clin Genet 78:381-7
Lemos C, Pereira-Monteiro J, Mendonça D, Ramos EM, Barros J, Sequeiros J, Alonso I , Sousa A (2010): Syntaxin 1A in migraine susceptibility: evidence for its involvement in a Portuguese study. Arch Neurol 67:422-7
Almeida T, Alonso I, Martins S, Ramos EM, Azevedo L, Ohno K, Amorim A, Saraiva-Pereira ML, Jardim LB, Matsuura T, Sequeiros J, Silveira I (2009): Ancestral origin of the ATTCT repeat expansion in spinocerebellar ataxia type 10 (SCA10). PLoS ONE 4: e4553
Alonso I, Marques JM, Sousa N, Sequeiros J, Olsson A, Silveira I (2008): Motor and cognitive deficits in the heterozygous leaner mouse, a Cav2.1 voltage-gated Ca2+ channel mutant. Neurobiol Aging 29:1733-1743
Martins S, Calafell F, Gaspar C, Wong VC, Silveira I, Nicholson GA, Brunt ER, Tranebjaerg L, Stevanin G, Hsieh M, Soong BW, Loureiro L, Dürr A, Tsuji S, Watanabe M, Jardim LB, Giunti P, Riess O, Ranum LP, Brice A, Rouleau GA, Coutinho P, Amorim A, Sequeiros J (2007): Asian origin for the worldwide-spread mutational event in Machado-Joseph disease. Arch Neurol 64:1502-1508
Loureiro, José Leal
Pereira Monteiro, José
Santos Moreda Graça, Mariana
Isabel da Silva Santos, Diana
Maria Lêdo da Silva Pinto, Susana
Morais, Sara Peres
Neto, João Martins
Pereira, Maria Conceição
Quintas Pinho, Marlene Sofia
Abreu Silva, Joana Patrícia