Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities

Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT) and involves a complex web of pathogenic mechanisms. Mutant HTT (mHTT) disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course. Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. Novel cerebrospinal fluid (CSF) and plasma biomarkers are among the earliest detectable changes in individuals with premanifest HD and have the sensitivity to detect therapeutic benefit. Therapeutically, the first human trial of an HTT-lowering antisense oligonucleotide successfully, and safely, reduced the CSF concentration of mHTT in individuals with HD. A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself

Spin and orbital states in La1.5 Sr0.5 CoO4 studied by electronic structure calculations

Electronic structure of the layered perovskite La1.5Sr0.5CoO4 with a checkerboard Co2+/Co3+ charge order is studied, using the local-spin-density approximation plus Hubbard U calculations including also the spin-orbit coupling and multiplet effect. Our results show that the Co2+ ion is in a high spin state (HS, t(2g)(5)e(g)(2)) and Co3+ low spin state (LS, t(2g)(6)). Due to a small Co2+ t(2g) crystal field splitting, the spin-orbit interaction produces an orbital moment of 0.26 mu(B) and accounts for the observed easy in-plane magnetism. Moreover, we find that the Co3+ intermediate spin state (IS, t(2g)(5)e(g)(1)) has a multiplet splitting of several tenths of eV and the lowest-lying one is still higher than the LS ground state by 120 meV, and that the Co3+ HS state (t(2g)(4)e(g)(2)) is more unstable by 310 meV. Either the IS or HS Co3+ ions would give rise to a wrong magnetic order and anisotropy

Towards automated characterisation of fatigue damage in composites using thermoelastic stress analysis

Composite materials demonstrate complicated fatigue behaviour due to their microstructure and the varied types of defects that can occur during loading. This necessitates experimentation to determine their performance under loading. In this study an algorithm is introduced for identifying and categorising different defects forming during fatigue tests. Thermoelastic stress analysis was used to obtain high spatial and temporal resolution stress information from the surface of notched composite specimens. Specimens with three different geometries were loaded in tension–tension fatigue to failure. An algorithm was used to identify when and where matrix cracking and delaminations formed within the specimens as well as quantify how this changed over time. By improving how damage events are identified and characterised, the algorithm reduces the amount of time needed to process experimental fatigue data and helps to provide greater understanding of fatigue processes in new materials from early small-scale cracking all the way to final failure

Huntington disease: natural history, biomarkers and prospects for therapeutics

Huntington disease (HD) can be seen as a model neurodegenerative disorder, in that it is caused by a single genetic mutation and is amenable to predictive genetic testing, with estimation of years to predicted onset, enabling the entire range of disease natural history to be studied. Structural neuroimaging biomarkers show that progressive regional brain atrophy begins many years before the emergence of diagnosable signs and symptoms of HD, and continues steadily during the symptomatic or 'manifest' period. The continued development of functional, neurochemical and other biomarkers raises hopes that these biomarkers might be useful for future trials of disease-modifying therapeutics to delay the onset and slow the progression of HD. Such advances could herald a new era of personalized preventive therapeutics. We describe the natural history of HD, including the timing of emergence of motor, cognitive and emotional impairments, and the techniques that are used to assess these features. Building on this information, we review recent progress in the development of biomarkers for HD, and potential future roles of these biomarkers in clinical trials

Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the R6/2 Mouse Model of HD

Huntington's disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6/2 mouse model of HD expresses a mutant version of exon 1 HTT and develops motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Despite the vast number of studies that have been performed on this model, the association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood. In an attempt to link these factors, we have performed longitudinal assessments of behavior (rotarod, open field, passive avoidance) and of regional brain abnormalities determined through magnetic resonance imaging (MRI) (whole brain, striatum, cortex, hippocampus, corpus callosum), as well as an end-stage histological assessment. Detailed correlative analyses of these three measures were then performed. We found a gender-dependent emergence of motor impairments that was associated with an age-related loss of regional brain volumes. MRI measurements further indicated that there was no striatal atrophy, but rather a lack of striatal growth beyond 8 weeks of age. T2 relaxivity further indicated tissue-level changes within brain regions. Despite these dramatic motor and neuroanatomical abnormalities, R6/2 mice did not exhibit neuronal loss in the striatum or motor cortex, although there was a significant increase in neuronal density due to tissue atrophy. The deposition of the mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the brain. End-stage histopathological assessments were not found to be as robustly correlated with the longitudinal measures of brain atrophy or motor impairments. In conclusion, modeling pre-manifest and early progression of the disease in more slowly progressing animal models will be key to establishing which changes are causally related. © 2013 Rattray et al

Probing electron-phonon interactions away from the Fermi level with resonant inelastic x-ray scattering

Interactions between electrons and lattice vibrations are responsible for a wide range of material properties and applications. Recently, there has been considerable interest in the development of resonant inelastic x-ray scattering (RIXS) as a tool for measuring electron-phonon ( e -ph) interactions. Here, we demonstrate the ability of RIXS to probe the interaction between phonons and specific electronic states both near to, and away from, the Fermi level. We perform carbon K -edge RIXS measurements on graphite, tuning the incident x-ray energy to separately probe the interactions of the π ∗ and σ ∗ electronic states. Our high-resolution data reveal detailed structure in the multiphonon RIXS features that directly encodes the momentum dependence of the e -ph interaction strength. We develop a Green’s-function method to model this structure, which naturally accounts for the phonon and interaction-strength dispersions, as well as the mixing of phonon momenta in the intermediate state. This model shows that the differences between the spectra can be fully explained by contrasting trends of the e -ph interaction through the Brillouin zone, being concentrated at the Γ and K points for the π ∗ states while being significant at all momenta for the σ ∗ states. Our results advance the interpretation of phonon excitations in RIXS and extend its applicability as a probe of e -ph interactions to a new range of out-of-equilibrium situations

Huntington's disease

Huntington’s disease is devastating to patients and their families — with autosomal dominant inheritance, onset typically in the prime of adult life, progressive course and combination of motor, cognitive and behavioural features. The disease is caused by an expanded CAG trinucleotide repeat (of variable length) in HTT, the gene which encodes the protein huntingtin. In mutation carriers, huntingtin is produced with abnormally long polyglutamine sequences that confers toxic gains of function and predispose the protein to fragmentation, resulting in neuronal dysfunction and death. In this Primer, we review the epidemiology of Huntington’s disease, noting that prevalence is higher than previously thought, geographically variable and increasing. We describe the relationship between CAG repeat length and clinical phenotype and the concept of genetic modifiers of the disease. We discuss normal huntingtin protein function, evidence for differential toxicity of mutant huntingtin variants, theories of huntingtin aggregation and the many different mechanisms of Huntington’s disease pathogenesis. We describe the genetic and clinical diagnosis of the condition, its clinical assessment and the multidisciplinary management of symptoms, given the absence of effective disease-modifying therapies. We review past and present clinical trials and therapeutic strategies under investigation, including impending trials of targeted huntingtin-lowering drugs and the progress in development of biomarkers that will support the next generation of trials

Hdac6 Knock-Out Increases Tubulin Acetylation but Does Not Modify Disease Progression in the R6/2 Mouse Model of Huntington's Disease

Huntington's disease (HD) is a progressive neurodegenerative disorder for which there is no effective disease modifying treatment. Following-on from studies in HD animal models, histone deacetylase (HDAC) inhibition has emerged as an attractive therapeutic option. In parallel, several reports have demonstrated a role for histone deacetylase 6 (HDAC6) in the modulation of the toxicity caused by the accumulation of misfolded proteins, including that of expanded polyglutamine in an N-terminal huntingtin fragment. An important role for HDAC6 in kinesin-1 dependent transport of brain-derived neurotrophic factor (BDNF) from the cortex to the striatum has also been demonstrated. To elucidate the role that HDAC6 plays in HD progression, we evaluated the effects of the genetic depletion of HDAC6 in the R6/2 mouse model of HD. Loss of HDAC6 resulted in a marked increase in tubulin acetylation throughout the brain. Despite this, there was no effect on the onset and progression of a wide range of behavioural, physiological, molecular and pathological HD-related phenotypes. We observed no change in the aggregate load or in the levels of soluble mutant exon 1 transprotein. HDAC6 genetic depletion did not affect the efficiency of BDNF transport from the cortex to the striatum. Therefore, we conclude that HDAC6 inhibition does not modify disease progression in R6/2 mice and HDAC6 should not be prioritized as a therapeutic target for HD

Hdac6 Knock-Out Increases Tubulin Acetylation but Does Not Modify Disease Progression in the R6/2 Mouse Model of Huntington's Disease

Huntington's disease (HD) is a progressive neurodegenerative disorder for which there is no effective disease modifying treatment. Following-on from studies in HD animal models, histone deacetylase (HDAC) inhibition has emerged as an attractive therapeutic option. In parallel, several reports have demonstrated a role for histone deacetylase 6 (HDAC6) in the modulation of the toxicity caused by the accumulation of misfolded proteins, including that of expanded polyglutamine in an N-terminal huntingtin fragment. An important role for HDAC6 in kinesin-1 dependent transport of brain-derived neurotrophic factor (BDNF) from the cortex to the striatum has also been demonstrated. To elucidate the role that HDAC6 plays in HD progression, we evaluated the effects of the genetic depletion of HDAC6 in the R6/2 mouse model of HD. Loss of HDAC6 resulted in a marked increase in tubulin acetylation throughout the brain. Despite this, there was no effect on the onset and progression of a wide range of behavioural, physiological, molecular and pathological HD-related phenotypes. We observed no change in the aggregate load or in the levels of soluble mutant exon 1 transprotein. HDAC6 genetic depletion did not affect the efficiency of BDNF transport from the cortex to the striatum. Therefore, we conclude that HDAC6 inhibition does not modify disease progression in R6/2 mice and HDAC6 should not be prioritized as a therapeutic target for HD