Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition.

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene (HTT). Although mutant HTT is expressed during embryonic development and throughout life, clinical HD usually manifests later in adulthood. A number of studies document neurodevelopmental changes associated with mutant HTT, but whether these are reversible under therapy remains unclear. Here, we identify very early behavioral, molecular, and cellular changes in preweaning transgenic HD rats and mice. Reduced ultrasonic vocalization, loss of prepulse inhibition, and increased risk taking are accompanied by disturbances of dopaminergic regulation in vivo, reduced neuronal differentiation capacity in subventricular zone stem/progenitor cells, and impaired neuronal and oligodendrocyte differentiation of mouse embryo-derived neural stem cells in vitro. Interventional treatment of this early phenotype with the histone deacetylase inhibitor (HDACi) LBH589 led to significant improvement in behavioral changes and markers of dopaminergic neurotransmission and complete reversal of aberrant neuronal differentiation in vitro and in vivo. Our data support the notion that neurodevelopmental changes contribute to the prodromal phase of HD and that early, presymptomatic intervention using HDACi may represent a promising novel treatment approach for HD.

Protein expression overlap: more important than which proteins change in expression?

In recent years, a large number of proteomics studies for various diseases were conducted, such as for cancer, cardiovascular and neurodegenerative disorders (NDs). The availability of huge data sets with a large number of differentially expressed proteins showed for the first time that not all protein changes between a diseased and a control state were specific. This review focuses on this protein expression overlap, specifically between NDs, and tries to investigate the possible reasons for this overlap by investigating 14 ND proteomics studies of Alzheimer's (six studies), Parkinson's (four studies) and Huntington's disease (three studies), as well as amyotrophic lateral sclerosis (one study). Studies were selected according to the availability of quantitative changes, number of (biological) repeats and numbers of proteins changed. The studies include investigations of human tissue and mouse, as well as cell culture, models. A change in metabolism-related proteins was found to be common among all disorders. These changes can be explained by alterations in key regulatory proteins, such as those involved in transcription. Since most NDs affect, at least initially, very specific areas of the brain, the location of the changes may be more important than the kind of protein alterations that occur, since they are very similar among NDs.