Genome-wide association meta-analysis of functional outcome after ischemic stroke

Neurology, Journal Year: 2019, Volume and Issue: 92(12)

Published: Feb. 23, 2019

To discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study.The study comprised 6,165 patients ischemic stroke from 12 studies in Europe, the United States, and Australia included GISCOME (Genetics of Ischaemic Stroke Functional Outcome) network. The primary outcome was modified Rankin Scale score after 60 to 190 days, evaluated as 2 dichotomous variables (0-2 vs 3-6 0-1 2-6) subsequently an ordinal variable. GWA analyses were performed each independently results meta-analyzed. Analyses adjusted for age, sex, severity (baseline NIH score), ancestry. significance level p < 5 × 10-8.We identified one variant functional (modified scores 0-2 3-6, = 5.3 10-9). This intronic (rs1842681) LOC105372028 gene is previously reported trans-expression quantitative trait locus PPP1R21, which encodes regulatory subunit protein phosphatase 1. ubiquitous implicated brain functions such plasticity. Several detected this demonstrated suggestive (p 10-5), some are within or near genes experimental evidence influence on volume and/or recovery (e.g., NTN4, TEK, PTCH1).In large stroke, we report significant several 3 months onset plausible mechanistic links recovery. Future replication exploration potential mechanisms warranted.

Language: Английский

---

Molecular mechanism of activation-triggered subunit exchange in Ca2+/calmodulin-dependent protein kinase II

eLife, Journal Year: 2016, Volume and Issue: 5

Published: March 7, 2016

Activation triggers the exchange of subunits in Ca2+/calmodulin-dependent protein kinase II (CaMKII), an oligomeric enzyme that is critical for learning, memory, and cardiac function. The mechanism by which subunit occurs remains elusive. We show human CaMKII holoenzyme exists dodecameric tetradecameric forms, calmodulin (CaM)-binding element can bind to hub destabilize it release dimers. structures from two distantly diverged organisms suggest CaM-binding activated acts as a wedge docking at intersubunit interfaces hub. This converts into spiral form or gain Our data reveal three-way competition element, whereby phosphorylation biases towards interface, away domain calmodulin, thus unlocking ability holoenzymes dimers with unactivated ones.

Language: Английский

---

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

Neuropsychopharmacology, Journal Year: 2016, Volume and Issue: 42(2), P. 524 - 539

Published: Aug. 23, 2016

Language: Английский

---

Structural Insights into the Regulation of Ca²⁺/Calmodulin-Dependent Protein Kinase II (CaMKII)

Cold Spring Harbor Perspectives in Biology, Journal Year: 2019, Volume and Issue: 12(6), P. a035147 - a035147

Published: Oct. 25, 2019

Moitrayee Bhattacharyya1,2,3, Deepti Karandur1,2,3 and John Kuriyan1,2,3,4,5 1Department of Molecular Cell Biology, University California, Berkeley, California 94720 2California Institute for Quantitative Biosciences (QB3), 3Howard Hughes Medical Institute, 4Department Chemistry, 5Physical Division, Lawrence Berkeley National Laboratory, Correspondence: kuriyan{at}berkeley.edu

Language: Английский

---

A neural m6A/Ythdf pathway is required for learning and memory in Drosophila

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: March 5, 2021

Abstract Epitranscriptomic modifications can impact behavior. Here, we used Drosophila melanogaster to study N 6 -methyladenosine (m A), the most abundant modification of mRNA. Proteomic and functional analyses confirm its nuclear (Ythdc1) cytoplasmic (Ythdf) YTH domain proteins as major m A binders. Assays short term memory in mutants reveal neural-autonomous requirements writers working via Ythdf, but not Ythdc1. Furthermore, A/Ythdf operate specifically mushroom body, center for associative learning. We map from wild-type Mettl3 mutant heads, allowing robust discrimination Mettl3-dependent sites that are highly enriched 5’ UTRs. Genomic indicate is preferentially deposited on genes with low translational efficiency does affect RNA stability. Nevertheless, tests a role activation. Altogether, our molecular genetic tissue-specific maps selective behavioral regulatory defects Mettl3/Ythdf pathway.

Language: Английский

---

Photoactivatable CaMKII induces synaptic plasticity in single synapses

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Feb. 2, 2021

Abstract Optogenetic approaches for studying neuronal functions have proven their utility in the neurosciences. However, optogenetic tools capable of inducing synaptic plasticity at level single synapses been lacking. Here, we engineered a photoactivatable (pa)CaMKII by fusing light-sensitive domain, LOV2, to CaMKIIα. Blue light or two-photon excitation reversibly activated paCaMKII. Activation spines was sufficient induce structural long-term potentiation (sLTP) vitro and vivo. paCaMKII activation also recruitment AMPA receptors functional LTP spines. By combining with protein activity imaging 2-photon FLIM-FRET, demonstrate that clustered induces robust sLTP via mechanism involves actin-regulatory small GTPase, Cdc42. This tool dissecting function CaMKII (i.e., sufficiency rather than necessity) manipulating will find many applications neuroscience other fields.

Language: Английский

---

Aberrant protein phosphorylation in Alzheimer disease brain disturbs pro-survival and cell death pathways

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2016, Volume and Issue: 1862(10), P. 1871 - 1882

Published: July 17, 2016

Language: Английский

---

Hippocampal molecular mechanisms involved in the enhancement of fear extinction caused by exposure to novelty

Proceedings of the National Academy of Sciences, Journal Year: 2014, Volume and Issue: 111(12), P. 4572 - 4577

Published: March 3, 2014

Significance Within a restricted time window, brief exposure to novel environment enhances the extinction of contextual fear. This can be explained by hippocampal process behaviorally induced synaptic tagging and capture. Here, we report that effect requires glutamate NMDA receptors L-voltage–dependent calcium channels involves activation calcium/calmodulin-dependent protein kinase II, in addition both ribosomal nonribosomal synthesis. All these mechanisms operate only when proteasomal-ubiquitin degradation system is intact, which suggests they depend on turnover. Extinction enhancement novelty great potential importance treatment fear memories, such as those posttraumatic stress disorder; treatments choice for conditions are based procedures.

Language: Английский

---

OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency

Molecular Psychiatry, Journal Year: 2017, Volume and Issue: 23(2), P. 444 - 458

Published: Jan. 10, 2017

Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction cortico-striato-thalamo-cortical (CSTC) circuits, dysregulated synaptic transmission have been implicated in pathogenesis OCD, underlying mechanisms remain largely unknown. Here we show that OCD-like behavior mice caused deficiency SPRED2, protein expressed various brain regions potent inhibitor Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting rodents, resulted facial skin lesions SPRED2 knockout (KO) mice. This was alleviated treatment with selective serotonin reuptake fluoxetine. In addition to previously suggested involvement cortico-striatal electrophysiological measurements revealed altered at thalamo-amygdala synapses morphological differences lateral amygdala neurons KO Changes function were accompanied expression pre- postsynaptic proteins amygdala. result transcription triggered upstream upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling Pathway overactivation mediated increased activity TrkB, Ras, ERK as specific not elicited elevated brain-derived neurotrophic factor levels. Using MEK selumetinib, suppressed TrkB/ERK-MAPK pathway vivo reduced grooming Altogether, this study identifies promising new regulator, novel mediating mechanism, critical circuitry involved OCD.

Language: Английский

---

Synapses, spines and kinases in mammalian learning and memory, and the impact of aging

Neuroscience & Biobehavioral Reviews, Journal Year: 2014, Volume and Issue: 50, P. 77 - 85

Published: July 4, 2014

Language: Английский

---