IntroductionHuntington disease (HD) is an autosomal-dominant neurodegenerative disorder caused by the pathogenic expansion of the polyglutamine (polyQ) N-terminal stretch in the huntingtin protein (HTT; encoded by HTT). HD is characterized by the dysfunction and death of neurons in the brain, leading to devastating cognitive, psychiatric, and motor symptoms in patients. Studies in multiple cell and animal model systems support the notion that polyQ expansion in mutant Htt leads to the gain of new toxic functions and loss of the neuroprotective functions of the WT Htt (1).Although some of its functions are linked to transcriptional activities in health and disease, Htt is primarily a cytoplasmic protein that associates with microtubules (MTs) and vesicles. Htt regulates intracellular trafficking of various organelles, including vesicles, by interacting with the dynein/dynactin pathway (2-4). Htt facilitates MT-dependent transport by interacting directly with dynein (2) and indirectly via huntingtin-associated protein 1 (HAP1), which binds to the dynactin p150 Glued subunit (3,(5)(6)(7). In pathological situations, the Htt-HAP1-dynactin complex is altered, resulting in a reduction of vesicular transport in neurons (3). These findings show that Htt integrates vesicular transport by regulating the activity of specific protein complexes containing the dynein/dynactin and kinesin 1 complexes and adaptor proteins such as HAP1.With 2 patterns of axonemal MTs (9 + 0 in primary cilia and 9 + 2 in motile cilia), cilia are involved in sensory role, motility, and flow generation. Within the last 5 years, the importance of this
In the developing cortex, projection neurons undergo multipolar-bipolar transition, radial-directed migration, and maturation. The contribution of these developmental steps to the structure of the adult cortex is not completely understood. Here, we report that huntingtin (HTT), the protein mutated in Huntington's disease, is enriched in polarizing projection neurons. The depletion of HTT in postmitotic projection neurons leads to the mislocalization of layer-specific neuronal populations in the mouse neocortex. HTT is required for the multipolar-bipolar transition of projection neurons and for the maintenance of their bipolar shape during their radial migration. HTT mediates these effects in vivo through the regulation of RAB11-dependent N-Cadherin trafficking. Importantly, HD pathological HTT alters RAB11-dependent neuronal migration. Finally, we show that the cortical defects resulting from the postmitotic loss of HTT specifically during embryonic development affect neuronal morphology at adulthood. Our data reveal a new HTT-RAB11-N-Cadherin pathway regulating multipolar-bipolar transition with direct implications for mature brain. VIDEO ABSTRACT.
BackgroundIt is suspected that excess of brain cholesterol plays a role in Alzheimer’s disease (AD). Membrane-associated cholesterol was shown to be increased in the brain of individuals with sporadic AD and to correlate with the severity of the disease. We hypothesized that an increase of membrane cholesterol could trigger sporadic AD early phenotypes.ResultsWe thus acutely loaded the plasma membrane of cultured neurons with cholesterol to reach the 30% increase observed in AD brains. We found changes in gene expression profiles that are reminiscent of early AD stages. We also observed early AD cellular phenotypes. Indeed we found enlarged and aggregated early endosomes using confocal and electron microscopy after immunocytochemistry. In addition amyloid precursor protein vesicular transport was inhibited in neuronal processes, as seen by live-imaging. Finally transient membrane cholesterol loading lead to significantly increased amyloid-β42 secretion.ConclusionsMembrane cholesterol increase in cultured neurons reproduces most early AD changes and could thus be a relevant model for deciphering AD mechanisms and identifying new therapeutic targets.Electronic supplementary materialThe online version of this article (doi:10.1186/1750-1326-9-60) contains supplementary material, which is available to authorized users.
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