Selective inhibition of phosphodiesterases 4, 5 and 9 induces HSP20 phosphorylation and attenuates amyloid beta 1-42 mediated cytotoxicity

Phosphodiesterase (PDE) inhibitors are currently under evaluation as agents that may facilitate the improvement of cognitive impairment associated with Alzheimer's disease. Our aim was to determine whether inhibitors of PDEs 4,5 and 9 could alleviate the cytotoxic effects of amyloid beta 1–42 (Aβ1-42) via a mechanism involving the small heatshock protein HSP20. We show that inhibition of PDEs 4,5 and 9 but not 3 induces the phosphorylation of HSP20 which, in turn, increases the co-localisation between the chaperone and Aβ1-42 to significantly decrease the toxic effect of the peptide. We conclude that inhibition of PDE9 is most effective to combat Aβ1-42 cytotoxicity in our cell model

PDE10A mutations help to unwrap the neurobiology of hyperkinetic disorders

The dual-specific cAMP/cGMP phosphodiesterase PDE10A is exclusively localised to regions of the brain and specific cell types that control crucial brain circuits and behaviours. The downside to this expression pattern is that PDE10A is also positioned to be a key player in pathology when its function is perturbed. The last decade of research has seen a clear role emerge for PDE10A inhibition in modifying behaviours in animal models of psychosis and Huntington's disease. Unfortunately, this has not translated to the human diseases as expected. More recently, a series of families with hyperkinetic movement disorders have been identified with mutations altering the PDE10A protein sequence. As these mutations have been analysed and characterised in other model systems, we are beginning to learn more about PDE10A function and perhaps catch a glimpse into how PDE10A activity could be modified for therapeutic benefit

Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme

A robust body of evidence supports the concept that phosphodiesterase 10A (PDE10A) activity in the basal ganglia orchestrates the control of coordinated movement in human subjects. Although human mutations in the PDE10A gene manifest in hyperkinetic movement disorders that phenocopy many features of early Huntington’s disease, characterization of the maladapted molecular mechanisms and aberrant signaling processes that underpin these conditions remains scarce. Recessive mutations in the GAF-A domain have been shown to impair PDE10A function due to the loss of striatal PDE10A protein levels, but here we show that this paucity is caused by irregular intracellular trafficking and increased PDE10A degradation in the cytosolic compartment. In contrast to GAF-A mutants, dominant mutations in the GAF-B domain of PDE10A induce PDE10A misfolding, a common pathological phenotype in many neurodegenerative diseases. These data demonstrate that the function of striatal PDE10A is compromised in disorders where disease-associated mutations trigger a reduction in the fidelity of PDE compartmentalization

Characterisation of PDE10A degradation and disease-associated mutations

No abstract available

Alcohol and the brain: from genes to circuits

Alcohol use produces wide-ranging and diverse effects on the central nervous system. It influences intracellular signaling mechanisms, leading to changes in gene expression, chromatin remodeling, and translation. As a result of these molecular alterations, alcohol affects the activity of neuronal circuits. Together, these mechanisms produce long-lasting cellular adaptations in the brain that in turn can drive the development and maintenance of alcohol use disorder (AUD). We provide an update on alcohol research, focusing on multiple levels of alcohol-induced adaptations, from intracellular changes to changes in neural circuits. A better understanding of how alcohol affects these diverse and interlinked mechanisms may lead to the identification of novel therapeutic targets and to the development of much-needed novel and efficacious treatment options

Untersuchung der thermisch initiierten Rissausbreitung an sproedbruechigen Materialien in verschiedener Atmosphaere

Available from TIB Hannover: RR 6084(60) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

RAB40C regulates RACK1 stability via theubiquitin–proteasome system

Aim: RACK1 is a multifunctional scaffolding protein that is expressed in many cellular compartments, orchestrating a number of signaling processes. RACK1 acts as a signaling hub to localize active enzymes to discrete locations; therefore tight control of RACK1 is vital to cellular homeostasis. Our aim was to identify the mechanisms responsible for RACK1 turnover and show that degradation is directed by the ubiquitin proteasome system. Results: Using siRNA screening, we identified RAB40C as the ubiquitin E3 ligase responsible for ubiquitination of RACK1, and that the action of RAB40C in controlling RACK1 levels is crucial to both cancer cell growth and migration of T cells. Conclusion: Our data suggest that manipulation of RACK1 levels in this way may provide a novel strategy to explore RACK1 function. Lay abstract: When cells in the body grow and divide there is a coordination underpinned by intra- and inter-cell communication. This process depends on anchoring proteins that bring cell communication proteins together in the correct amounts, in the correct place, and at the right time. RACK1 is a scaffolding protein that is known to fulfill this function and as a result a balance of cellular synthesis versus controlled breakdown tightly controls its concentration in cells. This study, for the first time, demonstrates that RACK1 concentration and function is controlled by another protein called RAB40C, which ‘tags’ it for destruction by the 26S proteasome. This may have therapeutic implications for certain kinds of cancerous cell growth

Differential Correlation of Serum BDNF and microRNA content in rats with rapid or late onset of heavy alcohol use

Heavy alcohol use reduces the levels of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex of rodents through the upregulation of microRNAs (miRs) targeting BDNF mRNA. In humans, an inverse correlation exists between circulating blood levels of BDNF and the severity of psychiatric disorders including alcohol abuse. Here, we set out to determine whether a history of heavy alcohol use produces comparable alterations in the blood of rats. We used an intermittent access to 20% alcohol using the two-bottle choice paradigm (IA20%2BC) and measured circulating levels of BDNF protein and miRs targeting BDNF in the serum of Long-Evans rats before and after 8 weeks of excessive alcohol intake. We observed that the drinking profile of heavy alcohol users is not unified, whereas 70% of the rats gradually escalate their alcohol intake (late onset), and 30% of alcohol users exhibit a very rapid onset of drinking (rapid onset). We found that serum BDNF levels are negatively correlated with alcohol intake in both rapid onset and late onset rats. In contrast, increased expression of the miRs targeting BDNF, miR30a-5p, miR-195-5p, miR191-5p and miR206-3p, was detected only in the rapid onset rats. Finally, we report that the alcohol-dependent molecular changes are not due to alterations in platelet number. Together, these data suggest that rats exhibit both late and rapid onset of alcohol intake. We further show that heavy alcohol use produces comparable changes in BDNF protein levels in both groups. However, circulating microRNAs are responsive to alcohol only in the rapid onset rats