That osteocalcin (OCN) is necessary for hippocampal-dependent memory and to prevent anxiety-like behaviors raises novel questions. One question is to determine whether OCN is also sufficient to ...improve these behaviors in wild-type mice, when circulating levels of OCN decline as they do with age. Here we show that the presence of OCN is necessary for the beneficial influence of plasma from young mice when injected into older mice on memory and that peripheral delivery of OCN is sufficient to improve memory and decrease anxiety-like behaviors in 16-mo-old mice. A second question is to identify a receptor transducing OCN signal in neurons. Genetic, electrophysiological, molecular, and behavioral assays identify
, an orphan G protein-coupled receptor expressed in neurons of the CA3 region of the hippocampus, as transducing OCN's regulation of hippocampal-dependent memory in part through inositol 1,4,5-trisphosphate and brain-derived neurotrophic factor. These results indicate that exogenous OCN can improve hippocampal-dependent memory in mice and identify molecular tools to harness this pathway for therapeutic purposes.
The Biology of Huntingtin Saudou, Frédéric; Humbert, Sandrine
Neuron (Cambridge, Mass.),
03/2016, Letnik:
89, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Huntingtin (HTT) is now a famous protein because an abnormal expansion of a glutamine stretch (polyQ) in its N-terminal sequence leads to the devastating neurodegenerative disorder Huntington’s ...disease (HD). The gene encoding huntingtin, HTT, and its dominantly inherited mutation were identified more than 20 years ago. Subsequently, in the hope of finding a cure for HD, there has been intense research aimed at understanding the molecular mechanisms underlying the deleterious effects of the presence of the abnormal polyQ expansion in HTT. Notwithstanding with the value of this approach, evidence has been emerging of a potential role of context and function of the HTT protein in the specificity and severity of the pathogenicity. HTT is ubiquitous both at the tissue and subcellular levels. It interacts with many partners and has long been considered having no clearly defined cellular function. Based on research over the past 20 years, specifically focused on the function of wild-type HTT, we reconsider the literature describing HTT-regulated molecular and cellular mechanisms that could be dysfunctional in HD and their possible physiological consequences for patients.
Mutation in huntingtin leads to Huntington’s disease. In this issue of Neuron, Saudou and Humbert highlight wild-type huntingtin-regulated molecular and cellular mechanisms that could be dysfunctional in Huntington‘s disease and the impact on the specificity and severity of this disorder.
Impaired hippocampal synaptic plasticity contributes to cognitive impairment in Huntington's disease (HD). However, the molecular basis of such synaptic plasticity defects is not fully understood. ...Combining live-cell nanoparticle tracking and super-resolution imaging, we show that AMPAR surface diffusion, a key player in synaptic plasticity, is disturbed in various rodent models of HD. We demonstrate that defects in the brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling pathway contribute to the deregulated AMPAR trafficking by reducing the interaction between transmembrane AMPA receptor regulatory proteins (TARPs) and the PDZ-domain scaffold protein PSD95. The disturbed AMPAR surface diffusion is rescued by the antidepressant drug tianeptine via the BDNF signaling pathway. Tianeptine also restores the impaired LTP and hippocampus-dependent memory in different HD mouse models. These findings unravel a mechanism underlying hippocampal synaptic and memory dysfunction in HD, and highlight AMPAR surface diffusion as a promising therapeutic target.
Dysfunctions in brain cholesterol homeostasis have been extensively related to brain disorders. The main pathway for brain cholesterol elimination is its hydroxylation into 24S-hydroxycholesterol by ...the cholesterol 24-hydrolase, CYP46A1. Increasing evidence suggests that CYP46A1 has a role in the pathogenesis and progression of neurodegenerative disorders, and that increasing its levels in the brain is neuroprotective. However, the mechanisms underlying this neuroprotection remain to be fully understood. Huntington's disease is a fatal autosomal dominant neurodegenerative disease caused by an abnormal CAG expansion in huntingtin's gene. Among the multiple cellular and molecular dysfunctions caused by this mutation, altered brain cholesterol homeostasis has been described in patients and animal models as a critical event in Huntington's disease. Here, we demonstrate that a gene therapy approach based on the delivery of CYP46A1, the rate-limiting enzyme for cholesterol degradation in the brain, has a long-lasting neuroprotective effect in Huntington's disease and counteracts multiple detrimental effects of the mutated huntingtin. In zQ175 Huntington's disease knock-in mice, CYP46A1 prevented neuronal dysfunctions and restored cholesterol homeostasis. These events were associated to a specific striatal transcriptomic signature that compensates for multiple mHTT-induced dysfunctions. We thus explored the mechanisms for these compensations and showed an improvement of synaptic activity and connectivity along with the stimulation of the proteasome and autophagy machineries, which participate to the clearance of mutant huntingtin (mHTT) aggregates. Furthermore, BDNF vesicle axonal transport and TrkB endosome trafficking were restored in a cellular model of Huntington's disease. These results highlight the large-scale beneficial effect of restoring cholesterol homeostasis in neurodegenerative diseases and give new opportunities for developing innovative disease-modifying strategies in Huntington's disease.
•Subtle changes in axonal transport can modulate protein accumulation at the synapse.•The huntingtin mutation underlying Huntington’s disease disrupts axonal transport.•Huntingtin (HTT) ...scaffolds/transports many key neuronal proteins, including BDNF.•Post-translational modifications in HTT regulate direction and speed of transport.•Tweaking HTT-mediated transport could help in Rett Syndrome and Alzheimer’s disease.
Over the past twenty years there have been numerous advances in our understanding of Huntington’s disease (HD) and other neurodegenerative proteopathies such as Alzheimer’s disease and Parkinson’s disease. In each case, disease-specific proteins are expressed and accumulate; what has been less clear is precisely what problems are caused by the accumulation. Recently we have begun to appreciate that increased protein levels or changes in the ratios of different isoforms affect the movement of molecules along the axon, thereby disrupting neuronal function. Huntingtin, the protein involved in HD, plays a special role in axonal transport, and very recent studies have found that its activity — and the movement of its cargoes — is altered not only in HD but in other neurological diseases. Here, we contextualize these studies and consider how modulating huntingtin activity could provide new avenues to therapy.
The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the ...cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner - a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.
Huntingtin (HTT), the protein mutated in Huntington's disease (HD), controls transport of the neurotrophin, brain-derived neurotrophic factor (BDNF), within corticostriatal neurons. Transport and ...delivery of BDNF to the striatum are reduced in disease, which contributes to striatal neuron degeneration. BDNF released by cortical neurons activates TrkB receptors at striatal dendrites to promote striatum survival. However, it remains to be determined whether transport of TrkB, the BDNF receptor, depends on HTT and whether such transport is altered in mutant situation. Here we show that TrkB binds to and colocalizes with HTT and dynein. Silencing HTT reduces vesicular transport of TrkB in striatal neurons. In HD, the polyQ expansion in HTT alters the binding of TrkB-containing vesicles to microtubules and reduces transport. Using a combination of microfluidic devices that isolate dendrites from cell bodies and BDNF coupled to quantum dots, we selectively analyzed TrkB retrograde transport in response to BDNF stimulation at dendrite terminals. We show that the retrograde transport of TrkB vesicles within striatal dendrites and the BDNF/TrkB-induced signaling through ERK phosphorylation and c-fos induction are decreased in neurons from an HD mouse model. Together, our findings demonstrate that HTT is a crucial regulator of TrkB trafficking. Transport defects in HD are not restricted to BDNF transport in cortical neurons but also affect trafficking of its ligand-bound receptor in the striatal neurons. This transport alteration may further impair BDNF-TrkB survival signaling within the corticostriatal connection that is most affected in HD.
Huntington’s disease (HD), a devastating neurodegenerative disorder, strongly affects the corticostriatal network, but the contribution of pre- and postsynaptic neurons in the first phases of disease ...is unclear due to difficulties performing early subcellular investigations in vivo. Here, we have developed an on-a-chip approach to reconstitute an HD corticostriatal network in vitro, using microfluidic devices compatible with subcellular resolution. We observed major defects in the different compartments of the corticostriatal circuit, from presynaptic dynamics to synaptic structure and transmission and to postsynaptic traffic and signaling, that correlate with altered global synchrony of the network. Importantly, the genetic status of the presynaptic compartment was necessary and sufficient to alter or restore the circuit. This highlights an important weight for the presynaptic compartment in HD that has to be considered for future therapies. This disease-on-a-chip microfluidic platform is thus a physiologically relevant in vitro system for investigating pathogenic mechanisms and for identifying drugs.
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•Microfluidic devices allow reconstitution of healthy and HD neuronal networks•High-resolution imaging in HD mature networks shows pre- and postsynaptic defects•HD corticostriatal network is defective and hypersynchronized•Genetic status of presynaptic neurons determines functionality of the network
Using microfluidics to reconstruct a Huntington’s disease corticostriatal network, Virlogeux et al. identify recurrent pre- and postsynaptic alterations leading to global circuit dysfunctions and hypersynchrony. They further demonstrate that the genetic status of the presynaptic compartment determines integrity of the network.
Striatum processes a wide range of functions including goal-directed behavior and habit formation, respectively encoded by the dorsomedial striatum (DMS) and dorsolateral striatum (DLS). GABAergic ...feedforward inhibition is known to control the integration of cortical information by striatal projection neurons (SPNs). Here we questioned whether this control is specific between distinct striatal functional territories. Using opto-activation and opto-inhibition of identified GABAergic interneurons, we found that different circuits are engaged in DLS and DMS, both ex vivo and in vivo: while parvalbumin interneurons efficiently control SPNs in DLS, somatostatin interneurons control SPNs in DMS. Moreover, both parvalbumin and somatostatin interneurons use a dual hyperpolarizing/depolarizing effect to control cortical input integration depending on SPN activity state: GABAergic interneurons potently inhibit spiking SPNs while in resting SPNs, they favor cortical activity summation via a depolarizing effect. Our findings establish that striatal GABAergic interneurons exert efficient territory-specific and state-dependent control of SPN activity and functional output.
Significance The normal function of the Huntingtin (HTT) protein is emerging. Here we report that selective autophagy requires an intact HTT protein in Drosophila and mouse CNS. We describe ...similarities in structure and binding activity between the C-terminal domain of HTT and the yeast autophagy scaffold protein Atg11, suggesting that HTT may normally function as a scaffold for various types of selective autophagy. Mice expressing an expanded repeat form of HTT also show deficits in protein clearance. Because autophagy is critical for clearance of cellular proteins, including mutant HTT, the impairment of normal HTT function by the polyQ expansion could suppress activity of the autophagy machinery. These results may have important implications when evaluating therapeutic strategies for HD.
Although dominant gain-of-function triplet repeat expansions in the Huntingtin ( HTT ) gene are the underlying cause of Huntington disease (HD), understanding the normal functions of nonmutant HTT protein has remained a challenge. We report here findings that suggest that HTT plays a significant role in selective autophagy. Loss of HTT function in Drosophila disrupts starvation-induced autophagy in larvae and conditional knockout of HTT in the mouse CNS causes characteristic cellular hallmarks of disrupted autophagy, including an accumulation of striatal p62/SQSTM1 over time. We observe that specific domains of HTT have structural similarities to yeast Atg proteins that function in selective autophagy, and in particular that the C-terminal domain of HTT shares structural similarity to yeast Atg11, an autophagic scaffold protein. To explore possible functional similarity between HTT and Atg11, we investigated whether the C-terminal domain of HTT interacts with mammalian counterparts of yeast Atg11-interacting proteins. Strikingly, this domain of HTT coimmunoprecipitates with several key Atg11 interactors, including the Atg1/Unc-51–like autophagy activating kinase 1 kinase complex, autophagic receptor proteins, and mammalian Atg8 homologs. Mutation of a phylogenetically conserved WXXL domain in a C-terminal HTT fragment reduces coprecipitation with mammalian Atg8 homolog GABARAPL1, suggesting a direct interaction. Collectively, these data support a possible central role for HTT as an Atg11-like scaffold protein. These findings have relevance to both mechanisms of disease pathogenesis and to therapeutic intervention strategies that reduce levels of both mutant and normal HTT.
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