Huntingtin is a protein that is mutated in Huntington's disease (HD), a dominant inherited neurodegenerative disorder. We previously proposed that, in addition to the gained toxic activity of the mutant protein, selective molecular dysfunctions in HD may represent the consequences of the loss of wild-type protein activity. We first reported that wild-type huntingtin positively affects the transcription of the brain-derived neurotrophic factor (

One cardinal feature of Huntington's disease (HD) is the degeneration of striatal neurons, whose survival greatly depends on the binding of cortical brain-derived neurotrophic factor (BDNF) with high-affinity (TrkB) and low-affinity neurotrophin receptors [p75 panneurotrophin receptor (p75 NTR )]. With a few exceptions, results obtained in HD mouse models demonstrate a reduction in cortical BDNF mRNA and protein, although autopsy data from a limited number of human HD cortices are conflicting. These studies indicate the presence of defects in cortical BDNF gene transcription and transport to striatum. We provide new evidence indicating a significant reduction in BDNF mRNA and protein in the cortex of 20 HD subjects in comparison with 17 controls, which supports the hypothesis of impaired BDNF production in human HD cortex. Analyses of the BDNF isoforms show that transcription from BDNF promoter II and IV is down-regulated in human HD cortex from an early symptomatic stage. We also found that TrkB mRNA levels are reduced in caudate tissue but not in the cortex, whereas the mRNA levels of T-Shc (a truncated TrkB isoform) and p75NTR are increased in the caudate. This indicates that, in addition to the reduction in BDNF mRNA, there is also unbalanced neurotrophic receptor signaling in HD.

Increasing evidence suggests that early neurodevelopmental defects in Huntington's disease (HD) patients could contribute to the later adult neurodegenerative phenotype. Here, by using HD-derived induced pluripotent stem cell lines, we report that early telencephalic induction and late neural identity are affected in cortical and striatal populations. We show that a large CAG expansion causes complete failure of the neuro-ectodermal acquisition, while cells carrying shorter CAGs repeats show gross abnormalities in neural rosette formation as well as disrupted cytoarchitecture in cortical organoids. Gene-expression analysis showed that control organoid overlapped with mature human fetal cortical areas, while HD organoids correlated with the immature ventricular zone/subventricular zone. We also report that defects in neuroectoderm and rosette formation could be rescued by molecular and pharmacological approaches leading to a recovery of striatal identity. These results show that mutant huntingtin precludes normal neuronal fate acquisition and highlights a possible connection between mutant huntingtin and abnormal neural development in HD.

The Repressor Element 1 Silencing Transcription factor (REST/NRSF) is a master repressor of neuronal programs in non-neuronal lineages shown to function as a central regulator of developmental programs and stem cell physiology. Aberrant REST function has been associated with a number of pathological conditions. In cancer biology, REST has been shown to play a tumor suppressor activity in epithelial cancers but an oncogenic role in brain childhood malignancies such as neuroblastoma and medulloblastoma. Here we examined REST expression in human glioblastoma multiforme (GBM) specimens and its role in GBM cells carrying self-renewal and tumorigenic competence. We found REST to be expressed in GBM specimens, its presence being particularly enriched in tumor cells in the perivascular compartment. Significantly, REST is highly expressed in self-renewing tumorigenic-competent GBM cells and its knock down strongly reduces their self-renewal in vitro and tumor-initiating capacity in vivo and affects levels of miR-124 and its downstream targets. These results indicate that REST contributes to GBM maintenance by affecting its self-renewing and tumorigenic cellular component and that, hence, a better understanding of these circuitries in these cells might lead to new exploitable therapeutic targets.

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SignificanceThe findings in this manuscript report on the identification of a posttranslational modification in the huntingtin protein (phosphorylation on residue T3 in the N17 region of the protein), which can revert the conformational effects of the Huntington’s disease (HD) mutation itself on the huntingtin protein and inhibit its aggregation properties in vitro. Using the first ultrasensitive immunoassay for a posttranslational modification of huntingtin protein, we demonstrate that pT3 levels are decreased in mutant huntingtin in preclinical models as well as in clinically relevant samples from HD patients. These findings are of high significance to Huntington’s disease biology, provide insights into mechanisms of Huntington’s disease pathogenesis, and open new opportunities for the development of therapeutics and diagnostics for Huntington’s disease.

Deciphering how the human striatum develops is necessary for understanding the diseases that affect this region. To decode the transcriptional modules that regulate this structure during development, we compiled a catalog of 1116 long intergenic noncoding RNAs (lincRNAs) identified de novo and then profiled 96,789 single cells from the early human fetal striatum. We found that D1 and D2 medium spiny neurons (D1- and D2-MSNs) arise from a common progenitor and that lineage commitment is established during the postmitotic transition, across a pre-MSN phase that exhibits a continuous spectrum of fate determinants. We then uncovered cell type–specific gene regulatory networks that we validated through in silico perturbation. Finally, we identified human-specific lincRNAs that contribute to the phylogenetic divergence of this structure in humans. This work delineates the cellular hierarchies governing MSN lineage commitment.

A variety of pathophysiological mechanisms are implicated in Huntington's disease (HD). Among them, reduced cholesterol biosynthesis has been detected in the HD mouse brain from presymptomatic stages, leading to diminished cholesterol synthesis, particularly in the striatum. In addition, systemic injection of cholesterol-loaded brain-permeable nanoparticles ameliorates synaptic and cognitive function in a transgenic mouse model of HD. To identify an appropriate treatment regimen and gain mechanistic insights into the beneficial activity of exogenous cholesterol in the HD brain, we employed osmotic mini-pumps to infuse three escalating doses of cholesterol directly into the striatum of HD mice in a continuous and rate-controlled manner. All tested doses prevented cognitive decline, while amelioration of disease-related motor defects was dose-dependent. In parallel, we found morphological and functional recovery of synaptic transmission involving both excitatory and inhibitory synapses of striatal medium spiny neurons. The treatment also enhanced endogenous cholesterol biosynthesis and clearance of mutant Huntingtin aggregates. These results indicate that cholesterol infusion to the striatum can exert a dose-dependent, disease-modifying effect and may be therapeutically relevant in HD.