N6-Furfuryladenine is protective in Huntington’s disease models by signaling huntingtin phosphorylation

© 2018 National Academy of Sciences. All Rights Reserved. The huntingtin N17 domain is a modulator of mutant huntingtin toxicity and is hypophosphorylated in Huntington’s disease (HD). We conducted high-content analysis to find compounds that could restore N17 phosphorylation. One lead compound from this screen was N6-furfuryladenine (N6FFA). N6FFA was protective in HD model neurons, and N6FFA treatment of an HD mouse model corrects HD phenotypes and eliminates cortical mutant huntingtin inclusions. We show that N6FFA restores N17 phosphorylation levels by being salvaged to a triphosphate form by adenine phosphoribosyltransferase (APRT) and used as a phosphate donor by casein kinase 2 (CK2). N6FFA is a naturally occurring product of oxidative DNA damage. Phosphorylated huntingtin functionally redistributes and colocalizes with CK2, APRT, and N6FFA DNA ad-ducts at sites of induced DNA damage. We present a model in which this natural product compound is salvaged to provide a triphosphate substrate to signal huntingtin phosphorylation via CK2 during low-ATP stress under conditions of DNA damage, with protective effects in HD model systems

PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically

Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion in the huntingtin (htt) gene. We found that peroxisome proliferator-activated receptor delta (PPARδ) interacts with htt and that mutant htt represses PPARδ-mediated transactivation. Increased PPARδ transactivation ameliorated mitochondrial dysfunction and improved cell survival of HD neurons. Expression of dominant-negative PPARδ in CNS was sufficient to induce motor dysfunction, neurodegeneration, mitochondrial abnormalities, and transcriptional alterations that recapitulated HD-like phenotypes. Expression of dominant-negative PPARδ specifically in the striatum of medium spiny neurons in mice yielded HD-like motor phenotypes, accompanied by striatal neuron loss. In mouse models of HD, pharmacologic activation of PPAR δ, using the agonist KD3010, improved motor function, reduced neurodegeneration, and increased survival. PPAR δ activation also reduced htt-induced neurotoxicity in vitro and in medium spiny-like neurons generated from human HD stem cells, indicating that PPAR δ activation may be beneficial in individuals with HD and related disorders

KIAA1109 Variants Are Associated with a Severe Disorder of Brain Development and Arthrogryposis.

Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-Kučinskas syndrome (MIM 617822). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Severe loss-of-function cases were incompatible with life, whereas those individuals with milder missense variants presented with severe global developmental delay, syndactyly of 2nd and 3rd toes, and severe muscle hypotonia resulting in incapacity to stand without support. Consistent with a causative role for KIAA1109 loss-of-function/hypomorphic variants in this syndrome, knockdowns of the zebrafish orthologous gene resulted in embryos with hydrocephaly and abnormally curved notochords and overall body shape, whereas published knockouts of the fruit fly and mouse orthologous genes resulted in lethality or severe neurological defects reminiscent of the probands' features.This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site

Etude des effets des peptides amyloïdes : du fonctionnement de la synapse aux modifications du cytosquelette dans l'apoptose neuronale.

Amyloid peptide accumulation is a key factor in Alzheimer's disease pathology. Forthis work, we have shown different effects of these peptides.We have shown the effects of different Aβ peptides on calcium currents ofhippocampal neurons. Thus, Aβ(25-35) increases type L calcium currents whereas Aβ(1-40)increases non-L type calcium currents.We next shown that Aβ application decreases evoked excitatory postsynaptic currentsand spontaneous miniature courants. These decreases are due to internalisation of AMPAreceptors and imply inflammatory processes and tranduction pathways activation.Finally, we shown that during apoptosis induced by amyloid peptide, class III β-tubulin is excluded from microtubules and forms cytoplasmic aggregates. These effects arenot due to changes in post-translationnal modifications of tubulin.L'accumulation du peptide amyloïde Aβ semble être le facteurs décisif dans laphysiopathologie de la maladie d'Alzheimer.Au cours de ce travail, nous avons montré différents effets de ces peptides.Nous avons montré les effets de différents types de peptides amyloïdes sur lescourants calciques des neurones de l'hippocampe. Ainsi, l'Aβ(25-35) augmente les courantscalciques de type L alors que l'Aβ(1-40) ceux de types non-L.Ensuite, l'application de peptide Aβ diminue les courants postsynaptiques excitateursévoqués mais également des courants miniatures spontanés. Ces diminutions seraient dues àune internalisation des récepteurs AMPA et impliquent des processus inflammatoires etl'activation de voies de transduction.Enfin, lors de l'apoptose neuronale induite par le peptide amyloïde la β-tubuline declasse III est exclue des microtubules et forme des agrégats cytoplasmiques. Ces effets ne sontpas dus à des changements dans les modifications post-traductionnelles de la tubuline

Late effects of cycle competition on arterial stiffness. A preliminary study.

International audienceAIM: The purpose of this study was to examine the effects of a cycle competition on the large arteries stiffness, 24-hours after the end of the effort. METHODS: Two males elite cyclists were studied before and after performing a stage-race. Their heart rate (HR) was measured continuously during the two competition days. The impact of the competition on their vascular system was determined using the measure of pulse wave velocity (PWV), an index of regional arterial stiffness. HR and blood pressure were also measured before and 24-hours postexercise. RESULTS: During the race, mean cyclists HR were relatively similar. Changes in PWV and HR were found after competition: these measures increased for the offensive subject and decreased for the other. CONCLUSIONS: Despite their involvement in the same cycling competition, we suggest that the long-term effects induced by effort on arterial stiffness were inverted according to the subject's comportment during the race. This study should be completed by others measures in order to precise our results and to precise the possible link between arteries stiffness and the recovery kinetic process, both depending on the cardiovascular autonomic nervous system control

Degree of Coordination between Breathing and Rhythmic Arm Movements During Hand Rim Wheelchair Propulsion

International audienc

Sox11 Reduces Caspase-6 Cleavage and Activity.

The apoptotic cascade is an orchestrated event, whose final stages are mediated by effector caspases. Regulatory binding proteins have been identified for caspases such as caspase-3, -7, -8, and -9. Many of these proteins belong to the inhibitor of apoptosis (IAP) family. By contrast, caspase-6 is not believed to be influenced by IAPs, and little is known about its regulation. We therefore performed a yeast-two-hybrid screen using a constitutively inactive form of caspase-6 for bait in order to identify novel regulators of caspase-6 activity. Sox11 was identified as a potential caspase-6 interacting protein. Sox11 was capable of dramatically reducing caspase-6 activity, as well as preventing caspase-6 self- cleavage. Several regions, including amino acids 117-214 and 362-395 within sox11 as well as a nuclear localization signal (NLS) all contributed to the reduction in caspase-6 activity. Furthermore, sox11 was also capable of decreasing other effector caspase activity but not initiator caspases -8 and -9. The ability of sox11 to reduce effector caspase activity was also reflected in its capacity to reduce cell death following toxic insult. Interestingly, other sox proteins also had the ability to reduce caspase-6 activity but to a lesser extent than sox11

Phosphorylation of mutant huntingtin at serine 116 modulates neuronal toxicity.

Phosphorylation has been shown to have a significant impact on expanded huntingtin-mediated cellular toxicity. Several phosphorylation sites have been identified on the huntingtin (Htt) protein. To find new potential therapeutic targets for Huntington's Disease (HD), we used mass spectrometry to identify novel phosphorylation sites on N-terminal Htt, expressed in HEK293 cells. Using site-directed mutagenesis we introduced alterations of phosphorylation sites in a N586 Htt construct containing 82 polyglutamine repeats. The effects of these alterations on expanded Htt toxicity were evaluated in primary neurons using a nuclear condensation assay and a direct time-lapse imaging of neuronal death. As a result of these studies, we identified several novel phosphorylation sites, validated several known sites, and discovered one phospho-null alteration, S116A, that had a protective effect against expanded polyglutamine-mediated cellular toxicity. The results suggest that S116 is a potential therapeutic target, and indicate that our screening method is useful for identifying candidate phosphorylation sites