Anorexia nervosa (AN), a disorder of voluntary food restriction leading to severe weight loss in female adolescents, remains an enigma. In particular, the appropriation of the starved thin body into ...the self-concept in AN is a process insufficiently researched and still poorly understood. Healthy humans undergoing starvation experience a slowing of movements and avoid voluntary exercise. By contrast, AN tends to be not infrequently associated with voluntary, sometimes excessive and/or compulsive exercise. Such deliberate exercise, not reported in starvation, seems to be facilitated by an increased urge for movement and physical restlessness, particular to AN. The increased urge to move would reflect spontaneous daily activity, the energy expended for everything that is not sleeping, eating, or voluntary exercise. Our hypothesis is that the starvation-induced increased urge to move and restlessness may promote the development of AN. Reversal of the fasting state, by either high caloric food or by leptin administration, would be expected to reduce restlessness and the increased urge to move along with improvement in other symptoms in AN. This review explores the idea that such restless activation in AN, in itself and through accelerating body weight loss, might foster the integration of the starving body into the self-concept by (1) enhancing the person’s sense of self-control and sense of achievement and (2) through invigorating proprioception and through intensifying the perception of the changing body shape. (3) Tentative evidence from studies piloting leptin administration in chronic AN patients which support this hypothesis is reviewed. The findings show that short term administration of high doses of leptin indeed mitigated depressive feelings, inner tension, intrusive thoughts of food, and the increased urge to be physically active, easing the way to recovery, yet had little influence on the patients’ personal commitment to remain at a low weight. Full recovery then requires resolution of the individuals’ personal unresolved psychological conflicts through psychotherapy and frequently needs specialized treatment approaches to address psychiatric co-morbidities. AN might be conceptualized as a hereditary form of starvation resistance, facilitated by the effects of starvation on fitness allowing for an exceptionally intense personal commitment to perpetuate food restriction.
•Axonal cargo entry depends on the presence of multiple subcompartments in the proximal axon.•Local mechanisms along the axon ensure the long-distance distribution of cargoes.•Microtubule associated ...proteins regulate motor-dependent axonal trafficking.
The polarized long-distance transport of neuronal cargoes depends on the presence of functional and structural axonal subcompartments. Given the heterogeneity of neuronal cargoes, selective sorting and entry occurs in the proximal axon where multiple subcellular specializations such as the axon initial segment, the pre-axonal exclusion zone, the MAP2 pre-axonal filtering zone and the Tau diffusion barrier provide different levels of regulation. Cargoes allowed to pass through the proximal axon spread into the more distal parts. Recent findings show that diverse cargo distributions along the axon depend on the compartmentalized organization of the cytoskeleton and the local regulation of multiple motor proteins by microtubule associated proteins. In this review, we focus on the local mechanisms that control cargo motility and discuss how they play a role in the overall circulation of axonal cargoes.
Intracellular transport in neurons is driven by molecular motors that carry many different cargos along cytoskeletal tracks in axons and dendrites. Identifying how motors interact with specific types ...of transport vesicles has been challenging. Here, we use engineered motors and cargo adaptors to systematically investigate the selectivity and regulation of kinesin-3 family member KIF1A–driven transport of dense core vesicles (DCVs), lysosomes, and synaptic vesicles (SVs). We dissect the role of KIF1A domains in motor activity and show that CC1 regulates autoinhibition, CC2 regulates motor dimerization, and CC3 and PH mediate cargo binding. Furthermore, we identify that phosphorylation of KIF1A is critical for binding to vesicles. Cargo specificity is achieved by specific KIF1A adaptors; MADD/Rab3GEP links KIF1A to SVs, and Arf-like GTPase Arl8A mediates interactions with DCVs and lysosomes. We propose a model where motor dimerization, posttranslational modifications, and specific adaptors regulate selective KIF1A cargo trafficking.
Dendritic spines are the primary postsynaptic sites of excitatory neurotransmission in the brain. They exhibit a remarkable morphological variety, ranging from thin protrusions, to stubby shapes, to ...bulbous mushroom shapes. The remodeling of spines is thought to regulate the strength of the synaptic connection, which depends vitally on the number and the spatial distribution of AMPA-type glutamate receptors (AMPARs). We present numerical and analytical analyses demonstrating that this shape strongly affects AMPAR diffusion. We report a pronounced suppression of the receptor exit rate out of spines with decreasing neck radius. Thus, mushroomlike spines become highly effective at retaining receptors in the spine head. Moreover, we show that the postsynaptic density further enhances receptor trapping, particularly in mushroomlike spines local exocytosis in the spine head, in contrast to release at the base, provides rapid and specific regulatory control of AMPAR concentration at synapses.
In neurons, polarized cargo distribution occurs mainly between the soma and axonal and dendritic compartments, and requires coordinated regulation of cytoskeletal remodeling and membrane trafficking. ...The Golgi complex plays a critical role during neuronal polarization and secretory trafficking has been shown to differentially transport proteins to both axons and dendrites. Besides the Golgi protein sorting, recent data revealed that palmitoylation cycles are an efficient mechanism to localize cytoplasmic, non-transmembrane proteins to particular neuronal compartments, such as the newly formed axon. Palmitoylation allows substrate proteins to bind to and ride with Golgi-derived secretory vesicles to all neuronal compartments. By allowing cytoplasmic proteins to ‘hitchhike’ on transport carriers in a non-polarized fashion, compartmentalized depalmitoylation may act as a selective retention mechanism.
The axon is the single long fiber that extends from the neuron and transmits electrical signals away from the cell body. The neuronal cytoskeleton, composed of microtubules (MTs), actin filaments and ...neurofilaments, is not only required for axon formation and axonal transport but also provides the structural basis for several specialized axonal structures, such as the axon initial segment (AIS) and presynaptic boutons. Emerging evidence suggest that the unique cytoskeleton organization in the axon is essential for its structure and integrity. In addition, the increasing number of neurodevelopmental and neurodegenerative diseases linked to defect in actin- and microtubule-dependent processes emphasizes the importance of a properly regulated cytoskeleton for normal axonal functioning. Here, we provide an overview of the current understanding of actin and microtubule organization within the axon and discuss models for the functional role of the cytoskeleton at specialized axonal structures.
Hypertrophic scarring and poor intrinsic axon growth capacity constitute major obstacles for spinal cord repair. These processes are tightly regulated by microtubule dynamics. Here, moderate ...microtubule stabilization decreased scar formation after spinal cord injury in rodents through various cellular mechanisms, including dampening of transforming growth factor-β signaling. It prevented accumulation of chondroitin sulfate proteoglycans and rendered the lesion site permissive for axon regeneration of growth-competent sensory neurons. Microtubule stabilization also promoted growth of central nervous system axons of the Raphe-spinal tract and led to functional improvement. Thus, microtubule stabilization reduces fibrotic scarring and enhances the capacity of axons to grow.
Interleukin-17: A Social Cytokine Hoogenraad, Casper C.; Riol-Blanco, Lorena
Cell,
04/2020, Letnik:
181, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Some children with autism spectrum disorder (ASD) show behavioral improvements when experiencing inflammation accompanied by fever; however, little is known about the mechanisms that underlie these ...beneficial effects. In a recent issue of Nature, Reed and colleagues demonstrate that the production of interleukin-17 (IL-17) during inflammation promotes social behavior in mouse models of neurodevelopmental disorders.
Nerve axons are shaped similar to long electric wires to quickly transmit information from one end of the body to the other. To remain healthy and functional, axons depend on a wide range of cellular ...cargos to be transported from the neuronal cell body to its distal processes. Because of the extended distance, a sophisticated and well-organized trafficking network is required to move cargos up and down the axon. Besides motor proteins driving cargo transport, recent data revealed that subcellular membrane specializations, including the axon initial segment at the beginning of the axon and the membrane-associated periodic skeleton, which extends throughout the axonal length, are important spatial regulators of cargo traffic. In addition, tubulin modifications and microtubule-associated proteins present along the axonal cytoskeleton have been proposed to bias cargo movements. Here, we discuss the recent advances in understanding these multiple layers of regulatory mechanisms controlling axonal transport.
Microtubule-based transport is essential for neuronal function because of the large distances that must be traveled by various building blocks and cellular materials. Recent studies in various model ...systems have unraveled several regulatory mechanisms and traffic rules that control the specificity, directionality and delivery of neuronal cargos. Local microtubule cues, opposing motor activity and cargo-adaptors that regulate motor activity control microtubule-based transport in neurons. Impairment of intracellular transport is detrimental to neurons and has emerged as a common factor in several neurological disorders. Genetic approaches have revealed strong links between intracellular transport processes and the pathogenesis of neurological diseases in both the central and peripheral nervous system. This Commentary highlights recent advances in these areas and discusses the transport defects that are associated with the development of neurological diseases.
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