A53T-alpha-synuclein-overexpression in the mouse nigrostriatal pathway leads to early increase of 14-3-3 epsilon and late increase of GFAP

Parkinson’s disease (PD) is a neurodegenerative disorder frequent at old age characterized by atrophy of the nigrostriatal projection. Overexpression and A53T-mutation of the presynaptic, vesicle-associated chaperone alpha-synuclein are known to cause early-onset autosomal dominant PD. We previously generated mice with transgenic overexpression of human A53T-alpha-synuclein (A53T-SNCA) in dopaminergic substantia nigra neurons as a model of early PD. To elucidate the early and late effects of A53T-alpha-synuclein on the proteome of dopaminergic nerve terminals in the striatum, we now investigated expression profiles of young and old mice using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) and mass spectrometry. In total, 15 proteins were upregulated and 2 downregulated. Mice before the onset of motor anomalies showed an upregulation of the spot containing 14-3-3 proteins, in particular the epsilon isoform, as well as altered levels of chaperones, vesicle trafficking and bioenergetics proteins. In old mice, the persistent upregulation of 14-3-3 proteins was aggravated by an increase of glial fibrillary acidic protein (GFAP) suggesting astrogliosis due to initial neurodegeneration. Independent immunoblots corroborated GFAP upregulation and 14-3-3 upregulation for the epsilon isoform, and also detected significant eta and gamma changes. Only for 14-3-3 epsilon a corresponding mRNA increase was observed in midbrain, suggesting it is transcribed in dopaminergic perikarya and accumulates as protein in presynapses, together with A53T-SNCA. 14-3-3 proteins associate with alpha-synuclein in vitro and in pathognomonic Lewy bodies of PD brains. They act as chaperones in signaling, dopamine synthesis and stress response. Thus, their early dysregulation probably reflects a response to alpha-synuclein toxicity

Precariousness in everyday life: homelessness in Japan

The Japanese social structure was established and has been maintained through a mixed economy comprising a balance between the state, the market, the family and the company. Vital elements in maintaining this balance have been the traditional family, full employment and increasing prosperity. More recently, developments have seen a reversal of economic prosperity, rising unemployment, increasing pressure to restructure the employment system and a potential rise in the number of households experiencing housing difficulties. In addition, the predominance of the nuclear family, the increased employment of women and decreased fertility has put the enterprise, family and state dynamic under challenge. This article explores some of the implications of these trends as some of the certainties of the past are giving way to increasing insecurity and risk across a wider section of society. It begins by exploring the institutional and social structure of post-war Japan, when there was little evidence of poverty and homelessness. It goes on to consider the recent rise in the number of people living on the streets of Japanese cities and the policies put in place. The article then outlines some of the processes of social change that have contributed to the growth in the numbers of homeless people in Japan. Copyright Joint Editors and Blackwell Publishing Ltd 2003.