Expanded polyglutamine (polyQ) repeats cause neurodegenerative disorders, but their cytotoxic structures remain to be elucidated. Although soluble polyQ oligomers have been proposed as a cytotoxic structure, the cytotoxicity of soluble polyQ oligomers, not inclusion bodies (IBs), has not been proven in living cells. To clarify the cytotoxicity of soluble polyQ oligomers, we carried our fluorescence resonance energy transfer (FRET) confocal microscopy and distinguished oligomers from monomers and IBs in a single living cell. FRET signals were detected when donor and acceptor fluorescent proteins were attached to the same side, not the opposite side, of polyQ repeats, which agrees with a parallel beta-sheet or a head-to-tail cylindrical beta-sheet model. These FRET signals disappeared in semi-intact cells, indicating that these polyQ oligomers are soluble. PolyQ monomers assembled into soluble oligomers in a length-dependent manner, which was followed by the formation of IBs. Notably, survival assay of neuronally differentiated cells revealed that cells with soluble oligomers died faster than those with IBs or monomers. These results indicate that a length-dependent formation of oligomers is an essential mechanism underlying neurodegeneration in polyQ-mediated disorders.

A series of highly extensive quinoidal oligothiophenes carrying a dicyanomethylene group at both terminal positions is synthesized. As the quinoidal structures extend, they have highly amphoteric abilities and show strong electronic absorptions in the visible to near-infrared region. The higher homologues, quinquethiophene and sexithiophene, exist as equilibrium mixtures with the biradical species.

We have evaluated the association between trunk deformities of the sagittal plane and functional impairment of daily living in community-dwelling elderly subjects. The analysis involved a detailed assessment of indoor and outdoor activities of daily living, satisfaction with life, and mental status. The participants in this study were 236 community-dwelling older adults, aged 65 years and older, living in Kahoku district of Kochi in Japan. The participants were classified based on their posture, which was assessed using photographs of the subjects, and interviewed to assess their basic activities of daily living (BADL), instrumental ADL (IADL), and cognitive well-being in the cross-sectional study. The statistical analysis was performed using the Mann-Whitney U-test. The lumbar kyphosis group received significantly lower BADL and IADL scores than the normal group. The trunk deformity group which were defined as kyphosis, flat back, and lumbar lordosis groups exhibited decreases in activities that included going out, shopping, depositing and withdrawing money, and visiting friends in the hospital. These activities require going outdoors; thus, this study showed that the trunk deformity group had limitations in outdoor activities. There was no significant difference between the geriatric depression score (GDS) and the pattern of posture. The abnormal trunk deformity groups tended to score lower than the normal group with regard to subjective healthiness and life satisfaction measures, including subjective health condition, everyday feeling, satisfaction with human relationships, satisfaction with economic condition, and satisfaction with present life.

Although the genetic basis of polyglutamine diseases has been recognized for 20 years, their molecular basis is still unclear. We have no therapeutic strategies for these intractable neurodegenerative disorders. To adequately treat patients, we must clarify the molecular basis of polyglutamine diseases. Three main issues address their molecular pathogenesis: whether the specific structure of expanded polyglutamine diseases results in cellular toxicity; what type of dysfunction causes them; and how the toxic structure causes dysfunction, that is, the link between structure and dysfunction. For structures, expanded polyglutamine proteins undergo transformation from monomers to oligomers and inclusions. One can hypothesize that one of these structures might cause the polyglutamine disease. Although the expanded polyglutamine protein is toxic, it does not explain the selective vulnerability of specific neurons in each polyglutamine disease. The normal function of each protein, including protein-protein interaction and modification, might also be crucial for pathogenesis. For dysfunction, various molecular mechanisms have been proposed, including dysregulation of transcription, impairment of the ubiquitin-proteasome system, mitochondrial dysfunction, dysregulation of intracellular Ca(2+) homeostasis, impairment of axonal transport and genotoxic stress. These hypotheses might correlate with each other. In addition, the disease pathogenesis of might not be exclusive to one particular structure or dysfunction. To develop a therapeutic strategy for patients with polyglutamine disease, identifying the most toxic structure and the earliest event in the pathogenesis is important. We review the current understanding of the toxic structure and dysfunction by expanded polyglutamine proteins and suggest directions for future studies of polyglutamine diseases.