Huntington’s disease (HD) is a fatal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion leading to an elongated polyglutamine stretch in Huntingtin1. Mutant Huntingtin (mHTT) is ubiquitously expressed but elicits selective cortical and striatal neurodegeneration in HD2. The mechanistic basis for such selective neuronal vulnerability remains unclear. A necessary step towards resolving this enigma is to define the cell types in which mHTT expression is causally linked to the disease pathogenesis. Using a conditional human genomic transgenic mouse model of HD expressing full-length mHTT (BACHD)3, we genetically reduced mHTT expression in striatal, cortical, or both neuronal populations. We show that cortical mHTT reduction in BACHD partially improves motor and psychiatric-like behavioral deficits, but does not improve neurodegeneration, while mHTT reduction in both neuronal populations consistently ameliorates all behavioral deficits and selective brain atrophy in this HD model. Furthermore, mHTT reduction in cortical or striatal neurons partially ameliorates cortico-striatal synaptic deficits, while further restoration of striatal synaptic function is achieved by mHTT reduction in both neuronal cell types. Our study demonstrates distinct, but interacting roles of cortical and striatal mHTT in disease pathogenesis and suggests that optimal HD therapeutics may require targeting mHTT in both cortical and striatal neurons.

Aging is often perceived as a degenerative process caused by random accrual of cellular damage over time. In spite of this, age can be accurately estimated by epigenetic clocks based on DNA methylation profiles from almost any tissue of the body. Since such pan-tissue epigenetic clocks have been successfully developed for several different species, it is difficult to ignore the likelihood that a defined and shared mechanism instead, underlies the aging process. To address this, we generated 10,000 methylation arrays, each profiling up to 37,000 cytosines in highly-conserved stretches of DNA, from over 59 tissue-types derived from 128 mammalian species. From these, we identified and characterized specific cytosines, whose methylation levels change with age across mammalian species. Genes associated with these cytosines are greatly enriched in mammalian developmental processes and implicated in age-associated diseases. From the methylation profiles of these age-related cytosines, we successfully constructed three highly accurate universal mammalian clocks for eutherians, and one universal clock for marsupials. The universal clocks for eutherians are similarly accurate for estimating ages (r>0.96) of any mammalian species and tissue with a single mathematical formula. Collectively, these new observations support the notion that aging is indeed evolutionarily conserved and coupled to developmental processes across all mammalian species - a notion that was long-debated without the benefit of this new and compelling evidence.

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Alzheimer's neurofibrillary tangles were studied by electron microscopy. The study includes four cases of Alzheimer's disease, two cases of atypical senile dementia, and one case of progressive supranuclear palsy. In Alzheimer's disease the tangles were composed of either straight filaments or paired helical filaments. In progressive supranuclear palsy the tangles were composed of 15 nm straight filaments or helical filaments. A few straight filaments were mixed with paired helical filaments. In atypical senile dementia, both straight and paired helical filaments comprised the tangles and one type of filaments appeared to intermingle with the other in the same neurons.