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