Role of endogenous cannabinoids in the control of basal ganglia activity

The cannabinoid system is a novel intercellular signaling system that plays a prominent role, among others, in the control of basal ganglia function. This finding can be concluded from the data obtained in different series of anatomical, biochemical, electrophysiological and pharmacological studies. These data demonstrated: (i) that the basal ganglia contain high levels of endocannabinoids and their receptors, mainly including the cannabinoid CB1 receptor subtype but also a related receptor type, the vanilloid TRPV1 receptor; (ii) that the activation or the blockade of this system produces important changes in motor behavior, changes that are originated as a consequence of interactions of the cannabinoid system with various classic neurotransmitters such as GABA, dopamine or glutamate; and (iii) the occurrence of marked changes in specific elements of the cannabinoid signaling system in various basal ganglia disorders, with emphasis in the induction/upregulation of the cannabinoid CB2 receptor subtype. This large evidence relating endocannabinoids and their receptors to the function of the basal ganglia, both in the healthy and the pathological brain, has provided support for the idea that cannabinoid-based medicines, with selectivity for different targets of the cannabinoid signaling system (synthetic enzymes, receptors, inactivation system), might have therapeutic potential to alleviate symptoms and/or provide neuroprotection in basal ganglia disorders, in particular Parkinson´s disease and Huntington´s chorea. The present chapter will review the knowledge on this issue trying to establish the future lines for the research on the therapeutic potential of the cannabinoid signaling system in basal ganglia disorders.peer-reviewe

IGF-1 receptor antagonism inhibits autophagy

Inhibition of the insulin/insulin-like growth factor signalling pathway increases lifespan and protects against neurodegeneration in model organisms, and has been considered as a potential therapeutic target. This pathway is upstream of mTORC1, a negative regulator of autophagy. Thus, we expected autophagy to be activated by insulin-like growth factor-1 (IGF-1) inhibition, which could account for many of its beneficial effects. Paradoxically, we found that IGF-1 inhibition attenuates autophagosome formation. The reduced amount of autophagosomes present in IGF-1R depleted cells can be, at least in part, explained by a reduced formation of autophagosomal precursors at the plasma membrane. In particular, IGF-1R depletion inhibits mTORC2, which, in turn, reduces the activity of protein kinase C (PKCa/b). This perturbs the actin cytoskeleton dynamics and decreases the rate of clathrin-dependent endocytosis, which impacts autophagosome precursor formation. Finally, with important implications for human diseases, we demonstrate that pharmacological inhibition of the IGF-1R signalling cascade reduces autophagy also in zebrafish and mice models. The novel link we describe here has important consequences for the interpretation of genetic experiments in mammalian systems and for evaluating the potential of targeting the IGF-1R receptor or modulating its signalling through the downstream pathway for therapeutic purposes under clinically relevant conditions, such as neurodegenerative diseases, where autophagy stimulation is considered beneficial.This is the version of the manuscript that was first published on line. The final version can be found published in Human Molecular Genetics by OUP here: http://hmg.oxfordjournals.org/content/22/22/4528.full.pdf+html

Complex inhibitory effects of nitric oxide on autophagy.

Autophagy, a major degradation process for long-lived and aggregate-prone proteins, affects various human processes, such as development, immunity, cancer, and neurodegeneration. Several autophagy regulators have been identified in recent years. Here we show that nitric oxide (NO), a potent cellular messenger, inhibits autophagosome synthesis via a number of mechanisms. NO impairs autophagy by inhibiting the activity of S-nitrosylation substrates, JNK1 and IKKβ. Inhibition of JNK1 by NO reduces Bcl-2 phosphorylation and increases the Bcl-2-Beclin 1 interaction, thereby disrupting hVps34/Beclin 1 complex formation. Additionally, NO inhibits IKKβ and reduces AMPK phosphorylation, leading to mTORC1 activation via TSC2. Overexpression of nNOS, iNOS, or eNOS impairs autophagosome formation primarily via the JNK1-Bcl-2 pathway. Conversely, NOS inhibition enhances the clearance of autophagic substrates and reduces neurodegeneration in models of Huntington's disease. Our data suggest that nitrosative stress-mediated protein aggregation in neurodegenerative diseases may be, in part, due to autophagy inhibition

Identification of MOAG-4/SERF as a Regulator of Age-Related Proteotoxicity

SummaryFibrillar protein aggregates are the major pathological hallmark of several incurable, age-related, neurodegenerative disorders. These aggregates typically contain aggregation-prone pathogenic proteins, such as amyloid-beta in Alzheimer's disease and alpha-synuclein in Parkinson's disease. It is, however, poorly understood how these aggregates are formed during cellular aging. Here we identify an evolutionarily highly conserved modifier of aggregation, MOAG-4, as a positive regulator of aggregate formation in C. elegans models for polyglutamine diseases. Inactivation of MOAG-4 suppresses the formation of compact polyglutamine aggregation intermediates that are required for aggregate formation. The role of MOAG-4 in driving aggregation extends to amyloid-beta and alpha-synuclein and is evolutionarily conserved in its human orthologs SERF1A and SERF2. MOAG-4/SERF appears to act independently from HSF-1-induced molecular chaperones, proteasomal degradation, and autophagy. Our results suggest that MOAG-4/SERF regulates age-related proteotoxicity through a previously unexplored pathway, which will open up new avenues for research on age-related, neurodegenerative diseases

Regulation of mammalian autophagy in physiology and pathophysiology

(Macro)autophagy is a bulk degradation process that mediates the clearance of long-lived proteins and organelles. Autophagy is initiated by double-membraned structures, which engulf portions of cytoplasm. The resulting autophagosomes ultimately fuse with lysosomes, where their contents are degraded. Although the term autophagy was first used in 1963, the field has witnessed dramatic growth in the last 5 years, partly as a consequence of the discovery of key components of its cellular machinery. In this review we focus on mammalian autophagy, and we give an overview of the understanding of its machinery and the signaling cascades that regulate it. As recent studies have also shown that autophagy is critical in a range of normal human physiological processes, and defective autophagy is associated with diverse diseases, including neurodegeneration, lysosomal storage diseases, cancers, and Crohn's disease, we discuss the roles of autophagy in health and disease, while trying to critically evaluate if the coincidence between autophagy and these conditions is causal or an epiphenomenon. Finally, we consider the possibility of autophagy upregulation as a therapeutic approach for various conditions.</jats:p