A-synuclein gene

Lewy bodies, neurofibrillary lesions and Pick bodies are intracellular filamentous inclusions. It is now well established that Lewy bodies are made of the protein a-synuclein and both neurofibrillary lesions and Pick bodies of the microtubule-associated protein tau. Mutations in the a-synuclein gene or an increase in its copy number cause autosomal-dominantly inherited forms of Parkinson s disease and dementia with Lewy bodies. Mutations in the tau gene cause a familial form of frontotemporal dementia. Here we review the evidence implicating a-synuclein and tau in these inherited and a number of sporadic neurodegenerative diseases. Collectively, a-synucleinopathies and tauopathies account for the vast majority of cases of late-onset neurodegenerative disease (Tables 45-1 and 45-2). 

Inactivation of the a-synuclein gene by homologous recombination results in mice that appear largely normal [3]. Analysis of mice lacking y-synuclein has similarly failed to reveal any gross abnormalities [4]. In hippocampal slices from mice without a-synuclein, the replenishment of docked vesicles by reserve pool vesicles was slower than in slices from control mice. It suggests a physiological role for a-synuclein in the mobilization of synaptic vesicles. 

FIGURE 45-2 Missense mutations in the a-synuclein gene and multiplication of the chromosomal region containing the a-synuclein gene cause autosomal-dominantly inherited forms of Parkinson s disease and dementia with Lewy bodies. The a-synuclein gene is shown schematically in green. 

Polymeropoulos, M.H. et al. Mutation in the a-synuclein gene identified in families with Parkinson s disease. Science 276 2045-2047,1997. 

Similarly, the discovery that the apolipoprotein E gene is strongly linked to late-onset Alzheimer s disease and that the a-synuclein gene is associated with Parkinson s disease raises the possibility of... 

Parkinson s disease is a common neurodegenerative syndrome characterized by loss of dopaminergic neurons in the substantia nigra, formation of filamentous intraneuronal inclusions (Lewy bodies) and an extrapyramidal movement disorder. Mutations in the a-synuclein gene are linked to familial Parkinson s disease, and a-synuclein accumulates in Lewy bodies and Lewy neurites. Normal and mutant forms of a-synuclein were expressed in Drosophila and produced adult-onset loss of dopaminergic neurons, filamentous intraneuronal inclusions containing a-synuclein and locomotor dysfunction. The Drosophila model thus recapitulates the essential features of the human disorder and makes possible a powerful genetic approach to Parkinson s disease. 

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