Molecular neurobiology of tau
Neurodegenerative diseases of the brain affect 5-10% of the population over the age of 65 and 30% over the age of 80. Alzheimer’s disease, the most common form of late-life dementia, is defined neuropathologically by the presence of abundant extracellular amyloid plaques and intracellular neurofibrillary lesions within certain brain regions. Of the two lesions, the neurofibrillary pathology correlates best with the presence of symptoms. This strong correlation is also seen in a number of other dementing disorders, where neurofibrillary lesions are found in the absence of amyloid deposits. It has been our belief over the years that nerve cells die in these diseases, because of the formation of the insoluble tau filaments that make up the neurofibrillary pathology. This view has received strong support with the recent discovery of mutations in the tau gene in a class of familial frontotemporal dementias with Parkinsonism (FTDP-17). If neurofibrillary lesions lead to nerve cell death, understanding the mechanisms of their formation is bound to lead to the development of effective therapies for all diseases with a filamentous tau pathology. At present, there is no experimental animal model for the filamentous tau protein pathology. The recent work on FTDP-17 offers novel approaches towards achieving this goal.
Parkinson’s disease and Dementia with Lewy bodies are also very common neurodegenerative disorders. They are characterised by the presence of abnormal filamentous deposits, named Lewy bodies, within some nerve cells which are believed to degenerate as a result. Unlike the filamentous deposits described above, the Lewy body filaments contain a-synuclein as their major component. Missense mutations have been described in a-synuclein in some familial forms of Parkinson’s disease, also in this disease a-synuclein is present in Lewy bodies. Recently, this protein has also been identified as the major component of glial cytoplasmic inclusions in multiple system atrophy. The new work offers for the first time the possibility to attempt to produce an experimental animal model for diseases with a-synuclein filamentous pathology such Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy.
The work in our laboratory is focused on the study of the mechanisms that induce neuronal and glial accumulation of tau and a-synuclein in neurodegenerative diseases of the brain and the role that these protein inclusions play in neuronal and glial death. We also aim to produce animal models for tauopathies and a-synucleinopathies.
The group of Dr Maria Grazia Spillantini includes:
- Oleg Anichtchik MD PhD
- Mariangela Iovino PhD
- Sujeong Yang PhD
- Marco Paoli PhD
- Manuela Mellone PhD Student
- Kristine Westmore Res Assistant
- Salvatore Valenti PhD Student
Iovino M., Patani R., Watts C., Chandran S., Spillantini MG. Microtubule associated tau protein expression in human stem cells derived neurons: a system where to study human tau function and dysfunction. PLoS One. 2010 Nov 11;5(11):e13947
Hampton D.W., Webber D.J., Bilican B., Goedert M., Spillantini M.G., Chandran C. Cell-mediated neuroprotection in a mouse model of human tauopathy. J Neurosci. 2010 Jul 28;30(30):9973-9983.
Garcia Reitböck P., Anichtchik O., Bellucci A., Iovino M., Ballini C.,, Fineberg E., Ghetti B., Della Corte L., Spano P.F., Tofaris G. K., Goedert, M., Spillantini M.G. SNARE protein redistribution and synaptic failure in a mouse model of Parkinson’s disease. Brain 2010 Jul;133(Pt 7):2032-44. Epub 2010 Jun 9.
Anderson JM, Hampton DW, Patani R, Pryce G, Crowther RA, Reynolds R, Franklin RJM, Giovannoni G, Compston DAS, Baker D, Spillantini MG, Chandran S: Abnormally phosphorylated tau is associated with neuronal and axonal loss in experimental autoimmune encephalomyelitis and multiple sclerosis. Brain 2008 Jul: 131 (7): 1736-48. Epub 2008 Jan 21.
Magnani E., Fan J., Gasparini L., Golding M., Williams M., Schiavo G., Goedert M., Amos L., Spillantini MG. : Interaction between tau and the dynactin complex. EMBO J. 2007 Oct 31;26(21):4546-54. Epub 2007 Oct 11.
Tofaris GK, Garcia Reitböck P., O’Connell M., Ghetti B., Humby T., Lambourne L., Gossage H., Emson P.C., Wilkinson L.S., Goedert M., Spillantini M.G.: Pathological changes in dopaminergic neurones in mice transgenic for human a-synuclein (1-120): implications for Lewy body disorders. J Neuroscience 26, 3942-3950, 2006.
Spillantini M.G., Murrell J.R., Goedert M., Farlow M.R., Klug A., Ghetti B.: Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proceedings of the National Academy of Sciences USA 95, 7737-7741, 1998.
Spillantini M.G., Crowther R.A., Jakes R., Hasegawa M., Goedert M.: a-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proceedings of the National Academy of Sciences USA 95, 6469-6473, 1998.