Autophagy lipidation machinery regulates axonal microtubule dynamics but is dispensable for survival of mammalian neurons.

Neurons maintain axonal homeostasis via employing a unique organization of the microtubule (MT) cytoskeleton, which supports axonal morphology and provides tracks for intracellular transport. Abnormal MT-based trafficking hallmarks the pathology of neurodegenerative diseases, but the exact mechanism regulating MT dynamics in axons remains enigmatic. Here we report on a regulation of MT dynamics by AuTophaGy(ATG)-related proteins, which previously have been linked to the autophagy pathway. We find that ATG proteins required for LC3 lipid conjugation are dispensable for survival of excitatory neurons and instead regulate MT stability via controlling the abundance of the MT-binding protein CLASP2. This function of ATGs is independent of their role in autophagy and requires the active zone protein ELKS1. Our results highlight a non-canonical role of ATG proteins in neurons and suggest that pharmacological activation of autophagy may not only promote the degradation of cytoplasmic material, but also impair axonal integrity via altering MT stability

Learning Mechanics and Game Mechanics Under the Perspective of Self-Determination Theory to Foster Motivation in Digital Game Based Learning

Background: Using digital games for educational purposes has been associated with higher levels of motivation among learners of different educational levels. However, the underlying psychological factors involved in digital game based learning (DGBL) have been rarely analyzed considering self-determination theory (SDT, Ryan \& Deci, 2000b); the relation of SDT with the flow experience (Csikszentmihalyi, 1990) has neither been evaluated in the context of DGBL

The State Dependent Impact of Bank Exposure on Sovereign Risk

The theoretical literature remains inconclusive on whether changes in bank exposure towards the domestic sovereign have an adverse effect on the sovereign risk position via a diabolic loop in the sovereign-bank nexus or reduce perceived default risk by acting as a disciplinary device for the sovereign. In this paper we empirically analyze the impact of exogenous changes in bank exposure on the risk position of the sovereign within a Markov switching structural vector autoregressive in heteroscedasticity (MSH-SVAR) framework for a set of EMU countries. We add to the methodological literature by allowing for regime dependent shock transmissions according to the volatility state of the financial system. Finding support for both, a stabilizing and a destabilizing effect, we document a clear clustering among the country sample: Rising bank exposure increased default risk for the EMU periphery, but decreased credit risk for the core EMU countries during times of financial stress

AP ‐2 reduces amyloidogenesis by promoting BACE 1 trafficking and degradation in neurons

Cleavage of amyloid precursor protein (APP) by BACE-1 (beta-site APP cleaving enzyme 1) is the rate-limiting step in amyloid-beta (A beta) production and a neuropathological hallmark of Alzheimer's disease (AD). Despite decades of research, mechanisms of amyloidogenic APP processing remain highly controversial. Here, we show that in neurons, APP processing and A beta production are controlled by the protein complex-2 (AP-2), an endocytic adaptor known to be required for APP endocytosis. Now, we find that AP-2 prevents amyloidogenesis by additionally functioning downstream of BACE1 endocytosis, regulating BACE1 endosomal trafficking and its delivery to lysosomes. AP-2 is decreased in iPSC-derived neurons from patients with late-onset AD, while conditional AP-2 knockout (KO) mice exhibit increased A beta production, resulting from accumulation of BACE1 within late endosomes and autophagosomes. Deletion of BACE1 decreases amyloidogenesis and mitigates synapse loss in neurons lacking AP-2. Taken together, these data suggest a mechanism for BACE1 intracellular trafficking and degradation via an endocytosis-independent function of AP-2 and reveal a novel role for endocytic proteins in AD

Structure-function integrity of the adult hippocampus depends on the transcription factor Bcl11b/Ctip2

© 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society. The dentate gyrus is one of the only two brain regions where adult neurogenesis occurs. Throughout life, cells of the neuronal stem cell niche undergo proliferation, differentiation and integration into the hippocampal neural circuitry. Ongoing adult neurogenesis is a prerequisite for the maintenance of adult hippocampal functionality. Bcl11b, a zinc finger transcription factor, is expressed by postmitotic granule cells in the developing as well as adult dentate gyrus. We previously showed a critical role of Bcl11b for hippocampal development. Whether Bcl11b is also required for adult hippocampal functions has not been investigated. Using a tetracycline-dependent inducible mouse model under the control of the forebrain-specific CaMKIIα promoter, we show here that the adult expression of Bcl11b is essential for survival, differentiation and functional integration of adult-born granule cell neurons. In addition, Bcl11b is required for survival of pre-existing mature neurons. Consequently, loss of Bcl11b expression selectively in the adult hippocampus results in impaired spatial working memory. Together, our data uncover for the first time a specific role of Bcl11b in adult hippocampal neurogenesis and function.Link_to_subscribed_fulltex

Gastric Helicobacter suis infection partially protects against neurotoxicity in a 6-OHDA Parkinson's disease mouse model

The exact etiology of Parkinson’s disease (PD) remains largely unknown, but more and more research suggests the involvement of the gut microbiota. Interestingly, idiopathic PD patients were shown to have at least a 10 times higher prevalence of Helicobacter suis (H. suis) DNA in gastric biopsies compared to control patients. H. suis is a zoonotic Helicobacter species that naturally colonizes the stomach of pigs and non-human primates but can be transmitted to humans. Here, we investigated the influence of a gastric H. suis infection on PD disease progression through a 6-hydroxydopamine (6-OHDA) mouse model. Therefore, mice with either a short- or long-term H. suis infection were stereotactically injected with 6-OHDA in the left striatum and sampled one week later. Remarkably, a reduced loss of dopaminergic neurons was seen in the H. suis/6-OHDA groups compared to the control/6-OHDA groups. Correspondingly, motor function of the H. suis-infected 6-OHDA mice was superior to that in the non-infected 6-OHDA mice. Interestingly, we also observed higher expression levels of antioxidant genes in brain tissue from H. suis-infected 6-OHDA mice, as a potential explanation for the reduced 6-OHDA-induced cell loss. Our data support an unexpected neuroprotective effect of gastric H. suis on PD pathology, mediated through changes in oxidative stress