Genetic murine models play an important role in the study of human neurological disorders by providing accurate and experimentally accessible systems to study pathogenesis and to test potential therapeutic treatments. One of the most widely employed models of Huntington's disease (HD) is the R6/2 transgenic mouse. To characterize this model further, we have performed behavioral and neuropathological analyses that provide a foundation for the use of R6/2 mice in preclinical therapeutic trials. Behavioral analyses of the R6/2 mouse reveal age-related impairments in dystonic movements, motor performance, grip strength, and body weight that progressively worsen until death. Significant neuropathological sequela, identified as increasing marked reductions in brain weight, are present from 30 days, whereas decreased brain volume is present from 60 days and decreased neostriatal volume and striatal neuron area, with a concomitant reduction in striatal neuron number, are present at 90 days of age. Huntingtin-positive aggregates are present at postnatal day 1 and increase in number and size with age. Our findings suggest that the R6/2 HD model exhibits a progressive HD-like behavioral and neuropathological phenotype that more closely corresponds to human HD than previously believed, providing further assurance that the R6/2 mouse is an appropriate model for testing potential therapies for HD.

Aging is a complex process involving intracellular changes and, notably, modifications in intercellular communications, required for coordinated responses to internal and external events. One of the potential reasons for such changes is an age-dependent failure of the integrating systems, including the circadian clock. Here we demonstrate that aging in a diurnal vertebrate, zebrafish (Danio rerio), is associated with major but selective circadian alterations. By 3-5 years of age, zebrafish have reduced amplitude and increased fragmentation of entrained circadian rhythms of activity, with fast desynchronization of the rhythms in the absence of environmental time cues. Aging in zebrafish is also associated with a reduction in the overall duration of nighttime sleep, followed by lower activity levels and a higher arousal threshold during the day. The production of the principal circadian hormone, melatonin, progressively declines during zebrafish aging. However, the ability of melatonin to acutely promote sleep and entrain circadian rhythms of activity remains robust until at least 4-5-years of age, consistent with the preserved levels of mRNA expression for melatonin receptors. Aged zebrafish have altered expression of the circadian genes zBmal1 and zPer1 but not zClock1. A lack of circadian time cues alters cognitive performance in aged more than in young zebrafish and this can be partially attenuated by daily melatonin administration. The advantages of zebrafish as a diurnal, small, prolific and genetically well-characterized vertebrate model provide new opportunities to clarify the intrinsic circadian factors involved in human aging and promote the search for prophylactic and treatment strategies.

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A nuclear gene from Saccharomyces cerevisiae was cloned by genetic complementation of a temperature-sensitive respiratory-deficient mutant. DNA sequence analysis reveals that it encodes a protein with homology to Yme1, FtsH and Tma, proteins which belong to the AAA-protein family (ATPases associated with diverse cellular activities). The members of this family are involved in very different biological processes. Yme1p, a yeast mitochondrial protein, affects the rate of DNA escape from mitochondria to the nucleus and the Escherichia coli FtsH protein is apparently involved in the post-translational processing of PBP3, a protein necessary for septation during cell division. This newly sequenced gene, which we have designated AFG3 for ATPase family gene 3, encodes a putative mitochondrial protein of 760 amino acid residues that is closely related to FtsH, Tma (protein from Lactococcus lactis) and Yme1p with 58, 55 and 46% identity respectively.

Three genes for mitochondrial proteins suppress null-mutations in both Afg3 and Rca1 when over-expressed Rep, M.; Nooy, J.; Guelin, E.J-M.; Grivell, L.A. Published in: Current Genetics DOI:10.1007/s002940050122Link to publication Citation for published version (APA):Rep, M., Nooy, J., Guelin, E. J-M., & Grivell, L. A. (1996). Three genes for mitochondrial proteins suppress nullmutations in both Afg3 and Rca1 when over-expressed. Current Genetics, 30, 206-211. DOI: 10.1007/s002940050122 General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Download date: 12 May 2018O R I G I N A L PA P E R Abstract The AFG3 gene of Saccharomyces cerevisiae encodes a mitochondrial inner membrane protein with ATP-dependent protease activity. To gain more insight into the function of this protein, multi-copy suppressors of an afg3-null mutation were isolated. Three genes were found that restored partial growth on non-fermentable carbon sources, all of which affect the biogenesis of respiratory competent mitochondria: PIM1(LON) encodes a matrixlocalized ATP-dependent protease involved in the turnover of matrix proteins; OXA1(PET1402) encodes a putative mitochondrial inner membrane protein involved in the biogenesis of the respiratory chain; and MBA1 encodes a mitochondrial protein required for optimal respiratory growth. All three genes also suppressed a null mutation in a related gene, RCA1, as well as in the combination of afg3-and rca1-null.