Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases.

Aging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases.

HERC1 Ubiquitin Ligase Is Required for Normal Axonal Myelination in the Peripheral Nervous System.

A missense mutation in HERC1 provokes loss of cerebellar Purkinje cells, tremor, and unstable gait in tambaleante (tbl) mice. Recently, we have shown that before cerebellar degeneration takes place, the tbl mouse suffers from a reduction in the number of vesicles available for release at the neuromuscular junction (NMJ). The aim of the present work was to study to which extent the alteration in HERC1 may affect other cells in the nervous system and how this may influence the motor dysfunction observed in these mice.

Mutation of the HERC 1 Ubiquitin Ligase Impairs Associative Learning in the Lateral Amygdala.

Tambaleante (tbl/tbl) is a mutant mouse that carries a spontaneous Gly483Glu substitution in the HERC1 (HECT domain and RCC1 domain) E3 ubiquitin ligase protein (HERC1). The tbl/tbl mutant suffers an ataxic syndrome given the almost complete loss of cerebellar Purkinje cells during adult life. More recent analyses have identified alterations at neuromuscular junctions in these mice, as well as in other neurons of the central nervous system, such as motor neurons in the spinal cord, or pyramidal neurons in the hippocampal CA3 region and the neocortex.

L1 retrotransposition alters the hippocampal genomic landscape enabling memory formation.

Somatic LINE-1 (L1) retrotransposition is a source of genomic mosaicism and potential phenotypic diversity among neurons during brain development. In the adult brain, L1 expression can be triggered by different environmental alterations, but its functional role in this context remains unknown. Here we demonstrate a neural activation-dependent increase in the number of L1 retrotransposon insertions in the hippocampus.

The HERC2 ubiquitin ligase is essential for embryonic development and regulates motor coordination.

A mutation in the HERC2 gene has been linked to a severe neurodevelopmental disorder with similarities to the Angelman syndrome. This gene codifies a protein with ubiquitin ligase activity that regulates the activity of tumor protein p53 and is involved in important cellular processes such as DNA repair, cell cycle, cancer, and iron metabolism. Despite the critical role of HERC2 in these physiological and pathological processes, little is known about its relevance in vivo.

Mutation in cytochrome b gene of mitochondrial DNA in a family with fibromyalgia is associated with NLRP3-inflammasome activation.

Background: Fibromyalgia (FM) is a worldwide diffuse musculoskeletal chronic pain condition that affects up to 5% of the general population. Many symptoms associated with mitochondrial diseases are reported in patients with FM such as exercise intolerance, fatigue, myopathy and mitochondrial dysfunction. In this study, we report a mutation in cytochrome b gene of mitochondrial DNA (mtDNA) in a family with FM with inflammasome complex activation.

Stress-Induced Depressive Behaviors Require a Functional NLRP3 Inflammasome.

Depression is a major public health concern in modern society, yet little is known about the molecular link between this condition and neuroinflammation. The inflammasome complex was recently shown to be implicated in depression. The present study shows the implication of NLRP3 inflammasome in animal model of stress-induced depression.

Updating stored memory requires adult hippocampal neurogenesis.

Adult hippocampal neurogenesis appears to influence hippocampal functions, such as memory formation for example. While adult hippocampal neurogenesis is known to be involved in hippocampal-dependent learning and consolidation processes, the role of such immature neurons in memory reconsolidation, a process involved in the modification of stored memories, remains unclear. Here, using a novel fast X-ray ablation protocol to deplete neurogenic cells, we have found that adult hippocampal neurogenesis is required to update object recognition stored memory more than to reinforce it.

AMPK Phosphorylation Modulates Pain by Activation of NLRP3 Inflammasome.

Aims: Impairment in adenosine monophosphate-activated protein kinase (AMPK) activity and NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation are associated with several metabolic and inflammatory diseases. In this study, we investigated the role of AMPK/NLRP3 inflammasome axis in the molecular mechanism underlying pain perception.

Results: Impairment in AMPK activation induced by compound C or sunitinib, two AMPK inhibitors, provoked hyperalgesia in mice (p<0.

Metformin and caloric restriction induce an AMPK-dependent restoration of mitochondrial dysfunction in fibroblasts from Fibromyalgia patients.

Impaired AMPK is associated with a wide spectrum of clinical and pathological conditions, ranging from obesity, altered responses to exercise or metabolic syndrome, to inflammation, disturbed mitochondrial biogenesis and defective response to energy stress. Fibromyalgia (FM) is a world-wide diffused musculoskeletal chronic pain condition that affects up to 5% of the general population and comprises all the above mentioned pathophysiological states. Here, we tested the involvement of AMPK activation in fibroblasts derived from FM patients.

Oxidative stress, mitochondrial dysfunction and, inflammation common events in skin of patients with Fibromyalgia.

Fibromyalgia is a chronic pain syndrome with unknown etiology. Recent studies have shown some evidence demonstrating that oxidative stress, mitochondrial dysfunction and inflammation may have a role in the pathophysiology of fibromyalgia. Despite several skin-related symptoms accompanied by small fiber neuropathy have been studied in FM, these mitochondrial changes have not been yet studied in this tissue.

Adult newborn neurons are involved in learning acquisition and long-term memory formation: the distinct demands on temporal neurogenesis of different cognitive tasks.

There is evidence that adult hippocampal neurogenesis influences hippocampal function, although the role these neurons fulfill in learning and consolidation processes remains unclear. Using a novel fast X-ray ablation protocol to deplete neurogenic cells, we demonstrate that immature adult hippocampal neurons are required for hippocampal learning and long-term memory formation. Moreover, we found that long-term memory formation in the object recognition and passive avoidance tests, two paradigms that involve circuits with distinct emotional components, had different temporal demands on hippocampal neurogenesis.

NLRP3 inflammasome is activated in fibromyalgia: the effect of coenzyme Q10.

Aims: Fibromyalgia (FM) is a prevalent chronic pain syndrome characterized by generalized hyperalgesia associated with a wide spectrum of symptoms such as fatigue and joint stiffness. Diagnosis of FM is difficult due to the lack of reliable diagnostic biomarkers, while treatment is largely inadequate. We have investigated the role of coenzyme Q10 (CoQ10) deficiency and mitochondrial dysfunction in inflammasome activation in blood cells from FM patients, and in vitro and in vivo CoQ10 deficiency models.

Can coenzyme q10 improve clinical and molecular parameters in fibromyalgia?

Fibromyalgia (FM) is a complex disorder that affects up to 5% of the general population worldwide. Its pathophysiological mechanisms are difficult to identify and current drug therapies demonstrate limited effectiveness. Both mitochondrial dysfunction and coenzyme Q10 (CoQ10) deficiency have been implicated in FM pathophysiology.

Is inflammation a mitochondrial dysfunction-dependent event in fibromyalgia?

Fibromyalgia (FM) is a complex disorder that affects up to 5% of the general population worldwide. Both mitochondrial dysfunction and inflammation have been implicated in the pathophysiology of FM. We have investigated the possible relationship between mitochondrial dysfunction, oxidative stress, and inflammation in FM.

Oral coenzyme Q10 supplementation improves clinical symptoms and recovers pathologic alterations in blood mononuclear cells in a fibromyalgia patient.

Fibromyalgia (FM) is a chronic pain syndrome with unknown etiology. Recent studies have shown evidence demonstrating that mitochondrial dysfunction and oxidative stress may have a role in the pathophysiology of FM. Coenzyme Q10 (CoQ10) is an essential electron carrier in the mitochondrial respiratory chain and a strong antioxidant.

Postnatal proteasome inhibition induces neurodegeneration and cognitive deficiencies in adult mice: a new model of neurodevelopment syndrome.

Defects in the ubiquitin-proteasome system have been related to aging and the development of neurodegenerative disease, although the effects of deficient proteasome activity during early postnatal development are poorly understood. Accordingly, we have assessed how proteasome dysfunction during early postnatal development, induced by administering proteasome inhibitors daily during the first 10 days of life, affects the behaviour of adult mice. We found that this regime of exposure to the proteasome inhibitors MG132 or lactacystin did not produce significant behavioural or morphological changes in the first 15 days of life.

Clinical symptoms in fibromyalgia are better associated to lipid peroxidation levels in blood mononuclear cells rather than in plasma.

Background: We examined lipid peroxidation (LPO) in blood mononuclear cells (BMCs) and plasma, as a marker of oxidative damage, and its association to clinical symptoms in Fibromyalgia (FM) patients.

Methods: We conducted a case-control and correlational study comparing 65 patients and 45 healthy controls. Clinical parameters were evaluated using the Fibromyalgia Impact Questionnaire (FIQ), visual analogues scales (VAS), and the Beck Depression Inventory (BDI).

The A-current modulates learning via NMDA receptors containing the NR2B subunit.

Synaptic plasticity involves short- and long-term events, although the molecular mechanisms that underlie these processes are not fully understood. The transient A-type K(+) current (I(A)) controls the excitability of the dendrites from CA1 pyramidal neurons by regulating the back-propagation of action potentials and shaping synaptic input. Here, we have studied how decreases in I(A) affect cognitive processes and synaptic plasticity.

Muscle physiology changes induced by every other day feeding and endurance exercise in mice: effects on physical performance.

Every other day feeding (EOD) and exercise induce changes in cell metabolism. The aim of the present work was to know if both EOD and exercise produce similar effects on physical capacity, studying their physiological, biochemical and metabolic effects on muscle. Male OF-1 mice were fed either ad libitum (AL) or under EOD.

Histone H1 poly[ADP]-ribosylation regulates the chromatin alterations required for learning consolidation.

Memory formation requires changes in gene expression, which are regulated by the activation of transcription factors and by changes in epigenetic factors. Poly[ADP]-ribosylation of nuclear proteins has been postulated as a chromatin modification involved in memory consolidation, although the mechanisms involved are not well characterized. Here we demonstrate that poly[ADP]-ribose polymerase 1 (PARP-1) activity and the poly[ADP]-ribosylation of proteins over a specific time course is required for the changes in synaptic plasticity related to memory stabilization in mice.

The M-current inhibitor XE991 decreases the stimulation threshold for long-term synaptic plasticity in healthy mice and in models of cognitive disease.

Aging, mental retardation, number of psychiatric and neurological disorders are all associated with learning and memory impairments. As the underlying causes of such conditions are very heterogeneous, manipulations that can enhance learning and memory in mice under different circumstances might be able to overcome the cognitive deficits in patients. The M-current regulates neuronal excitability and action potential firing, suggesting that its inhibition may increase cognitive capacities.

From learning to forgetting: behavioral, circuitry, and molecular properties define the different functional states of the recognition memory trace.

Neuropsychological analyses of amnesic patients, as well as lesion experiments, indicate that the temporal lobe is essential for the encoding, storage, and expression of object recognition memory (ORM). However, temporal lobe structures directly involved in the consolidation and reconsolidation of these memories are not yet well-defined. We report here that systemic administration of a protein synthesis inhibitor before or up to 4 h after training or reactivation sessions impairs consolidation and reconsolidation of ORM, without affecting short-term memory.

Lack of DREAM protein enhances learning and memory and slows brain aging.

Memory deficits in aging affect millions of people and are often disturbing to those concerned. Dissection of the molecular control of learning and memory is paramount to understand and possibly enhance cognitive functions. Old-age memory loss also has been recently linked to altered Ca(2+) homeostasis.