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Yu D, Zarate N, White A, Coates D, Tsai W, Nanclares C, Cuccu F, Yue JS, Brown TG, Mansky RH, Jiang K, Kim H, Nichols-Meade T, Larson SN, Gundry K, Zhang Y, Tomas-Zapico C, Lucas JJ, Benneyworth M, Öz G, Cvetanovic M, Araque A, Gomez-Pastor R

Huntington's disease (HD) is a neurodegenerative disease resulting in devastating motor, cognitive, and psychiatric deficits. The striatum is a brain region that controls movement and some forms of cognition and is most significantly impacted in HD. However, despite well-documented deficits in learning and memory in HD, knowledge of the potential implication of other brain regions such as the hippocampus remains limited. Here, we study the comparative impact of enhanced mHTT aggregation and neuropathology in the striatum and hippocampus of two HD mouse models. We utilized the zQ175 as a control HD mouse model and the Q175DN mice lacking the PGK-Neomycin cassette generated in house. We performed a comparative characterization of the neuropathology between zQ175 and Q175DN mice in the striatum and the hippocampus by assessing HTT aggregation, neuronal and glial pathology, chaperone expression, and synaptic density. We showed that Q175DN mice presented enhanced mHTT aggregation in both striatum and hippocampus compared to zQ175. Striatal neurons showed a greater susceptibility to enhanced accumulation of mHTT than hippocampal neurons in Q175DN despite high levels of mHTT in both regions. Contrary to the pathology seen in the striatum, Q175DN hippocampus presented enhanced spare capacity showing increased synaptic density, decreased Iba1 microglia density and enhanced HSF1 levels in specific subregions of the hippocampus compared to zQ175. Q175DN mice are a valuable tool to understand the fundamental susceptibility differences to mHTT toxicity between striatal neurons and other neuronal subtypes. Furthermore, our findings also suggest that cognitive deficits observed in HD animals might arise from either striatum dysfunction or other regions involved in cognitive processes but not from hippocampal degeneration.

Protein Kinase CK2 is a holoenzyme composed of two regulatory subunits (CK2β) and two catalytic subunits (CK2α and CK2α′). CK2 controls several cellular processes including proliferation, inflammation, and cell death. However, CK2α and CK2α′ possess different expression patterns and substrates and therefore impact each of these processes differently. Elevated CK2α participates in the development of cancer, while increased CK2α′ has been associated with neurodegeneration, especially Huntington′s disease (HD). HD is a fatal disease for which no effective therapies are available. Genetic deletion of CK2α′ in HD mouse models has ameliorated neurodegeneration. Therefore, pharmacological inhibition of CK2α′ presents a promising therapeutic strategy for treating HD. However, current CK2 inhibitors are unable to discriminate between CK2α and CK2α′ due to their high structural homology, especially in the targeted ATP binding site. Using computational analyses, we found a potential Type IV (″D″ pocket) allosteric site on CK2α′ that contained different residues than CK2α and was distal from the ATP binding pocket featured in both kinases. With this potential allosteric site in mind, we screened a commercial library containing ≈29,000 allosteric-kinase-inhibitor-like compounds using a CK2α′ activity-dependent ADP-GloTM Kinase assay. Obtained hits were counter-screened against CK2α revealing two CK2α′ selective compounds. These two compounds might serve as the basis for further medicinal chemistry optimization for the potential treatment of HD.Competing Interest StatementThe authors have declared no competing interest.

ObjectiveTo study efficacy and safety of escalating doses of canakinumab, a fully human anti-IL-1β monoclonal antibody in the severe cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease (NOMID).Methods6 patients were enrolled in this 24-month, open-label phase I/II study. All underwent anakinra withdrawal. The initial subcutaneous canakinumab dose was 150 mg (or 2 mg/kg in patients ≤40 kg) or 300 mg (or 4 mg/kg) with escalation up to 600 mg (or 8 mg/kg) every 4 weeks. Full remission was remission of patient-reported clinical components and measures of systemic inflammation and CNS inflammation. Hearing, vision and safety were assessed. Primary endpoint was full remission at month 6.ResultsAll patients flared after anakinra withdrawal, and symptoms and serum inflammatory markers improved with canakinumab. All patients required dose escalation to the maximum dose. At month 6, none had full remission, although 4/6 achieved inflammatory remission, based on disease activity diary scores and normal C-reactive proteins. None had CNS remission; 5/6 due to persistent CNS leucocytosis. At the last study visit, 5/6 patients achieved inflammatory remission and 4/6 had continued CNS leucocytosis. Visual acuity and field were stable in all patients, progressive hearing loss occurred in 1/10 ears. Adverse events (AEs) were rare. One serious AE (abscess due to a methicillin-resistant Staphylococcus aureus infection) occurred.ConclusionsCanakinumab at the studied doses improves symptoms and serum inflammatory features of NOMID, although low-grade CNS leukocytosis in four patients and headaches in one additional patient persisted. Whether further dose intensifications are beneficial in these cases remains to be assessed.ClinicalTrials.gov identifierNCT00770601.