In postnatal testes, follicle-stimulating hormone (FSH) acts on somatic Sertoli cells to activate gene expression directly via an intracellular signaling pathway composed of cAMP, cAMP-dependent protein kinase (PKA), and cAMP-response element-binding protein (CREB), and promotes germ cell development indirectly. Yet, the paracrine factors mediating the FSH effects to germ cells ...

We have previously reported that 5α-dihydrotestosterone (DHT) inhibits FSH-mediated granulosa cell proliferation by reducing cyclin D2 mRNA expression and blocking cell cycle progression at G1/S phase. The present study investigated the role of AMP activated protein kinase (AMPK) in DHT-mediated inhibition of granulosa cell proliferation. Granulosa cells harvested from 3-d ...

BACKGROUNDChemerin is a novel adipokine involved in the regulation of adipocyte development, inflammation and metabolic functions. To date, no role of this adipokine in reproductive functions has been described. In the present study, we identified chemerin and its receptor, CMKLR1 (chemokine-like receptor 1), in primary human granulosa cells (hGCs) and ...

The final number of Sertoli cells reached during the proliferative periods determines sperm production capacity in adulthood. It is well known that FSH is the major Sertoli cell mitogen; however, little is known about the signal transduction pathways that regulate the proliferation of Sertoli cells. The hypothesis of this investigation ...

The stress kinase mitogen-activated protein kinase kinase 7 (MKK7) is a specific activator of c-Jun N-terminal kinase (JNK), which controls various physiological processes such as cell proliferation, apoptosis, differentiation and migration. Here we show that genetic inactivation of MKK7 resulted in an extended period of oscillation in circadian gene expression ...

Casein kinase 1 delta (CK1δ) and its closest homolog CK1ε are key regulators of diverse cellular growth and survival processes such as Wnt signaling, DNA repair and circadian rhythms. We report three crystal structures of the kinase domain of human CK1δ, one apo and two complexed with a potent and ...

Mood disorders are considered to be associated with altered circadian rhythms, but the correlation between them has remained obscure. The mood stabilizer, lithium, is an inhibitor of glycogen synthase kinase-3β (GSK-3β), which is a modulator of the circadian clock system. Here, we show that chronic restraint (CR) stress diminishes behavioral ...

Even though peripheral circadian oscillators in the cardiovascular system are known to exist, the daily rhythms of the cardiovascular system are mainly attributed to autonomic or hormonal inputs under the control of the central oscillator, the suprachiasmatic nucleus (SCN). In order to examine the role of peripheral oscillators in the ...

Mounting evidence suggests that PERIOD (PER) proteins play a central role in setting the speed (period) and phase of the circadian clock. Pharmacological and genetic studies have shown that changes in PER phosphorylation kinetics are associated with changes in circadian rhythm period and phase, which can lead to sleep disorders ...

Circadian rhythms are autoregulatory, endogenous rhythms with a period of approximately 24 h. A wide variety of physiological and molecular processes are regulated by the circadian clock in organisms ranging from bacteria to humans. Phosphorylation of clock proteins plays a critical role in generating proper circadian rhythms. Casein Kinase 2 ...

In the course of a day, the Neurospora clock protein FREQUENCY (FRQ) is progressively phosphorylated at up to 113 sites and eventually degraded. Phosphorylation and degradation are crucial for circadian time keeping, but it is not known how phosphorylation of a large number of sites correlates with circadian degradation of ...

ABSTRACT: BACKGROUND: It is now widely accepted that AMP-activated protein kinase (AMPK) is a critical regulator of energy homeostasis. Recently, it has been shown to regulate circadian clocks. In seasonal breeding species such as sheep, the circadian clock controls the secretion of an endogenous rhythm of melatonin and, as a ...

Robust circadian oscillations of the proteins PERIOD (PER) and TIMELESS (TIM) are hallmarks of a functional clock in the fruitfly Drosophila melanogaster. Early morning phosphorylation of PER by the kinase Doubletime (DBT) and subsequent PER turnover is an essential step in the functioning of the Drosophila circadian clock. Here using ...

Altered neurogenesis has been reported in Alzheimer disease (AD), the most common neurodegenerative disorder characterized with hyperphosphorylated tau and accumulation of β-amyloid (Aβ). Recent studies suggest that tau phosphorylation is essential for hippocampal neurogenesis, however, it is not known whether tau phosphorylation also play a role in neurogenesis of subventricular ...

Microtubules are involved in the formation of axons and dendrites, maintenance of neuronal morphology, and cellular trafficking. Recent studies suggest that drugs affecting dopamine activity in the brain can induce cytoskeletal modifications. For instance, we have demonstrated in acute rat brain slices a molecular chain of events connecting dopamine D1 ...

Circadian clocks coordinate the timing of important biological processes. Interconnected transcriptional and post-translational feedback loops based on a set of clock genes generate and maintain these rhythms with a period of about 24 hours. Many clock proteins undergo circadian cycles of post-translational modifications. Among these modifications, protein phosphorylation plays an ...

Synchronous oscillations of thousands of cellular clocks in the suprachiasmatic nucleus (SCN), the circadian centre, are coordinated by precisely timed cell-cell communication, the principle of which is largely unknown. Here we show that the amount of RGS16 (regulator of G protein signalling 16), a protein known to inactivate Gαi, increases ...

The circadian clock in the cyanobacterium Synechococcus elongatus is composed of a post-translational oscillator (PTO) that can be reconstituted in vitro from three different proteins in the presence of ATP and a transcription-translation feedback loop (TTFL). The homo-hexameric KaiC kinase, phosphatase and ATPase alternates between hypo- and hyper-phosphorylated states over ...

Glycogen synthase kinase-3α (GSK-3α) and GSK-3β are intracellular kinases with largely redundant functions. However, the deletion of each GSK-3 isoform in the mouse has distinct consequences, suggesting that these related enzymes also have non-overlapping isoform-specific functions. A yeast two-hybrid screen for GSK-3α interacting partners revealed an interaction with the Receptor ...

Ectodomain shedding of the amyloid precursor protein (APP) by the metalloprotease activity α-secretase is a key regulatory event preventing the generation of the Alzheimer's disease (AD) amyloid β peptide. Proteases similar to α-secretase are essential for diverse physiological processes, such as embryonic development, cell adhesion and neuronal guidance. Previously, several ...

Unraveling the biochemical and genetic alterations that control the aggregation of protein tau is crucial to understand the etiology of tau-related neurodegenerative disorders. We expressed wild type and six clinical frontotemporal dementia with parkinsonism (FTDP) mutants of human protein tau in wild-type yeast cells and cells lacking Mds1 or Pho85, ...

Mitogen activated protein kinase (MAPK) cascade is evolutionally preserved in all eukaryotic cells, and regulates various cellular activities such as gene expression, mitosis, differentiation, and apoptosis. Recently, Bashor et al. have shown that Ste5 scaffold protein can be used to reshape the MAPK cascade through engineered feedback loops, and have ...

Molecular chaperones regulate the aggregation of a number of proteins that pathologically misfold and accumulate in neurodegenerative diseases. Identifying ways to manipulate these proteins in disease models is an area of intense investigation; however, the translation of these results to the mammalian brain has progressed more slowly. In this study, ...

Cyclin-dependent kinase (Cdk)5 is a proline-directed Ser/Thr protein kinase that functions mainly in neurons and is activated by binding to a regulatory subunit, p35 or p39. Kinase activity is mainly determined by the amount of p35 available, which is controlled by a balance between synthesis and degradation. Kinase activity is ...

It is well established that lead (Pb) exposure in humans leads to learning and memory impairment. However, the biological and molecular mechanisms are still not clearly understood. When over activated, serine/threonine protein phosphatases are known to function as a constraint on learning and memory. Activation of these phosphatases can also ...

In recent decades, the study of the amyloid precursor protein (APP) and of its proteolytic products carboxy terminal fragment (CTF), APP intracellular C-terminal domain (AICD) and amyloid beta has been mostly focussed on the role of APP as a producer of the toxic amyloid beta peptide. Here, we reconsider the ...

Histamine H(3) receptor antagonists enhance cognition in preclinical models and have been proposed as novel therapeutics for cognitive disorders, in particular Alzheimer's disease (AD). Increased neurotransmitter (e.g. acetylcholine and histamine) release associated with this pharmacology may lead to activation of postsynaptic signaling pathways relevant to cognition and neuroprotection, such as ...

Precise regulation of cyclin-dependent kinase 5 (Cdk5), a member of the cyclin-dependent kinase family, is critical for proper neuronal development and functions. Cdk5 is activated through its association with the neuron-specific activator p35 or p39. Nonetheless, how its kinase activity is regulated in neurons is not well understood. In this ...

Neuroinflammation and associated neuronal dysfunction mediated by activated microglia play an important role in the pathogenesis of Alzheimer disease (AD). Microglia are activated by aggregated forms of amyloid-β protein (Aβ), usually demonstrated in vitro by stimulating microglia with micromolar concentrations of fibrillar Aβ, a major component of amyloid plaques in ...

Alzheimer's disease is a major cause of dementia for which treatments remain unsatisfactory. Cyclin-dependent kinase 5 (CDK5) is a relevant kinase that has been hypothesized to contribute to the tau pathology. Several classes of chemical inhibitors for CDK5 have been developed, but they generally lack the specificity to distinguish among ...

The amyloid cascade hypothesis of Alzheimer's disease (AD) posits that the generation of β-amyloid (Aβ) triggers Tau neurofibrillary pathology. Recently a "17 kD" calpain-induced Tau fragment, comprising residues 45-230 (molecular weight [MW], 18.7 kD), was proposed to mediate Aβ-induced toxicity. Here, we demonstrate that the "17 kD" fragment is actually ...

Manganese has long been known to induce neurological degenerative disorders. Emerging evidence indicates that hyperphosphorylated tau is associated with neurodegenerative diseases, but whether such hyperphosphorylation plays a role in manganese-induced neurotoxicity remains unclear. To fill this gap, we investigated the effects of manganese on tau phosphorylation in PC12 cells. In ...

Mammalian glycogen synthase kinase-3 (GSK3) is generated from two genes, GSK3α and GSK3β, while a splice variant of GSK3β (GSK3β2), containing a 13 amino acid insert, is enriched in neurons. GSK3α and GSK3β deletions generate distinct phenotypes. Here, we show that phosphorylation of CRMP2, CRMP4, β-catenin, c-Myc, c-Jun and some ...

Double-stranded RNA dependent kinase (PKR) is a pro-apoptotic kinase that controls protein translation. Previous studies revealed that activated PKR is increased in brains with Alzheimer's disease (AD). Glycogen Synthase Kinase Aβ (GSK-3β) is responsible for tau phosphorylation and controls several cellular functions also including apoptosis. The goal of this work ...

Previous studies have shown that progesterone modulates the activity of different kinases and the phosphorylation of Tau in the brain. These actions of progesterone may be involved in the hormonal regulation of neuronal differentiation, neuronal function, and neuroprotection. However, the action of progesterone on protein phosphatases in the nervous system ...

Tau protein is a prominent component of paired helical filaments in Alzheimer's disease (AD) and other tauopathies. While the abnormal phosphorylation of tau on serine and threonine has been well established in the disease process, its phosphorylation on tyrosine has only recently been described. We previously showed that the Src ...

Intraneuronal tau aggregations are distinctive pathological features of Parkinson's disease (PD) with autosomal-dominant mutations in leucine-rich repeat kinase 2 (LRRK2). The most prevalent LRRK2 mutation, G2019S (glycine to serine substitution at amino acid 2019), causes neurite shrinkage through unclear pathogenetic mechanisms. We found that expression of G2019S mutant in Drosophila ...

Neurodegenerative tauopathies characterized by hyperphosphorylated tau include frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) and Alzheimer's disease (AD). Reducing tau levels improves cognitive function in mouse models of AD and FTDP-17, but the mechanisms regulating the turnover of pathogenic tau are unknown. We found that tau is acetylated ...

Neuronal cell cycle reentry, which is associated with aberrant tau phosphorylation, is thought to be a mechanism of neurodegeneration in AD. Caffeine is a neuroprotective drug known to inhibit the cell cycle, suggesting that its neuroprotective nature may rely, at least in part, on preventing tau abnormalities secondary to its ...

Aggregation of amyloid-beta (Abeta) and Tau protein are hallmarks of Alzheimer's disease (AD), and according to the Abeta-cascade hypothesis, Abeta is considered toxic for neurons and Tau a downstream target of Abeta. We have investigated differentiated primary hippocampal neurons for early localized changes following exposure to Abeta oligomers. Initial events ...

Neurodegeneration induced by abnormal hyperphosphorylation and aggregation of the microtubule-associated protein tau defines neurodegenerative tauopathies. Destabilization of microtubules by loss of tau function and filament formation by toxic gain of function are two mechanisms suggested for how abnormal tau triggers neuronal loss. Recent experiments in kinesin-1 deficient mice suggested that ...

A principal feature of the progression of Alzheimer's disease (AD) is the appearance of aberrant phosphorylation of the microtubule-associated protein tau in the brains of affected individuals. Significant research efforts have been directed at identifying the kinases involved in this process, as well as developing pharmacological agents to inhibit these ...

In traumatic brain injury (TBI) there is often compression of the cerebral cortex. Using a rat epidural bead implantation model we found that mechanical compression distorted the dendrites of underlying cortical pyramidal neurons, and that the deformed dendrites regained straight morphology in 3 days. This was accompanied by a transient ...

Cyclin-dependent kinase 5 (Cdk5) plays a key role in the development of the mammalian nervous system; it phosphorylates a number of targeted proteins involved in neuronal migration during development to synaptic activity in the mature nervous system. Its role in the initial stages of neuronal commitment and differentiation of neural ...

High levels of the adipocytokine leptin are associated with reduced risk of Alzheimer's disease. Leptin treatment also reduces β-amyloid (Aβ) levels in in vivo and in vitro models of Alzheimer's disease. Aβ and leptin interact with the Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. Akt/mTORC1 activation reduces tau ...

Leucine-rich repeat kinase-2 (LRRK2) mutations are a common cause of Parkinson's disease. Here we identify inhibitors of LRRK2 kinase that are protective in in vitro and in vivo models of LRRK2-induced neurodegeneration. These results establish that LRRK2-induced degeneration of neurons in vivo is kinase dependent and that LRRK2 kinase inhibition ...

The dual-specificity tyrosine(Y)-phosphorylation-regulated kinase 1A (Dyrk1A) gene is located on human chromosome 21 and encodes a proline-directed protein kinase that might be responsible for mental retardation and early onset of Alzheimer's disease (AD) in Down syndrome (DS) patients. Presenilin 1 (PS1) is a key component of the γ-secretase complex in ...

Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-β peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated Tau protein. Tau is mostly found in a hyperphosphorylated form in these tangles. Glycogen synthase kinase 3β (GSK3β) is a proline-directed kinase generally considered as one ...

Synuclein is a soluble, natively unfolded protein that is highly enriched in the presynaptic terminals of neurons in the central nervous system. Interest in -synuclein has increased markedly following the discovery of a relationship between its dysfunction and several neurodegenerative diseases, including Parkinson's disease. The physiological functions of -synuclein remain ...

NMR spectroscopy was used to explore the different aspects of the normal and pathological functions of tau, but proved challenging because the protein contains 441 amino acids and has poor signal dispersion. We have set out to dissect the phosphorylation patterns of tau in order to understand better its role ...