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The effects of synuclein null mutations on murine physiology and development

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RobertsonD_2005redux.pdf (31.94Mb)
Date
2005
Author
Robertson, Darren
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Abstract
 
 
The synuclein family came into the limelight with the discovery oftwo point mutations in the human a-synuclein gene associated with autosomal dominant, familial Parkinson's disease. This triggered numerous studies aimed at understanding the mechanism of a-synuclein involvement in neurodegeneration. Fibrillated asynuclein has been identified as a major component of Lewy bodies in dopaminergic neurones of the substantia nigra pars compacta (SNpc) in cases of idiopathic Parkinson's disease as well as other diseases in which inclusions feature now known as synucleinopathies. Moreover, it has been demonstrated that a-synuclein can aggregate in vitro into filaments structurally similar to filaments found in pathological inclusions and that mutated forms of human a-synuclein aggregate substantially faster than wild-type protein. These results suggested a causative role of a-synuclein aggregation in the development of synucleinopathies.
 
We studied the effects of a targeted inactivation of y-synuclein and later a-synuclein and α/γ-synuclein together on murine physiology and development. These animals are viable and fertile with no gross physiological of morphological abnormalities. A quantitative evaluation ofthe substantia nigra showed a reduction in the number of dopaminergic neurones in the SNpc region but not in ventral tegmental area (VTA) of adult γ-synuclein null mutant mice. Similar reductions were revealed in asynuclein and double α/γ-synuclein null mutant animals, this difference appearing after birth and remaining constant throughout life. However, in none of these mutants did this lead to significant changes in levels of striatal dopamine or dopamine metabolite levels or motor function.
 
In all three studied types of null mutants, dopaminergic neurones of SNpc were resistant to l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) toxicity. We propose that both synucleins are important for effective survival of some SNpc neurones during a critical period of development and that, in the absence of these proteins, permanent activation of compensatory mechanisms allow many neurones to survive and become resistant to certain toxic insults.
 
We have shown that the absence of α-, γ- or α- and γ-synuclein does not precipitate any obvious or serious developmental or functional abnormalities. Ifthe synuclein family are important for the correct development of the SNpc then compensatory mechanisms exist to limit the effect oftheir absence, not giving rise to any visible deleterious phenotype.
 
URI
http://hdl.handle.net/1842/29967
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