c-Abl kinase at the crossroads of healthy synaptic remodeling and synaptic dysfunction in neurodegenerative diseases

Our ability to learn and remember depends on the active formation,remodeling,and elimination of synapses.Thus,the development and growth of synapses as well as their weakening and elimination are essential for neuronal rewiring.The structural reorganization of synaptic complexes,changes in actin cytos keleton and organelle dynamics,as well as modulation of gene expression,determine synaptic plasticity.It has been proposed that dys regulation of these key synaptic homeostatic processes underlies the synaptic dysfunction observed in many neurodegenerative diseases.Much is known about downstream signaling of activated N-methyl-D-aspartate andα-amino-3-hydroxy-5-methyl-4-isoazolepro pionate receptors;howeve r,other signaling pathways can also contribute to synaptic plasticity and long-lasting changes in learning and memory.The non-receptor tyrosine kinase c-Abl(ABL1)is a key signal transducer of intra and extracellular signals,and it shuttles between the cyto plasm and the nucleus.This review focuses on c-Abl and its synaptic and neuronal functions.Here,we discuss the evidence showing that the activation of c-Abl can be detrimental to neurons,promoting the development of neurodegenerative diseases.Nevertheless,c-Abl activity seems to be in a pivotal balance between healthy synaptic plasticity,regulating dendritic spines remodeling and gene expression after cognitive training,and synaptic dysfunction and loss in neurodegenerative diseases.Thus,c-Abl genetic ablation not only improves learning and memory and modulates the brain genetic program of trained mice,but its absence provides dendritic spines resiliency against damage.Therefo re,the present review has been designed to elu cidate the common links between c-Abl regulation of structural changes that involve the actin cytos keleton and organelles dynamics,and the transc riptional program activated during synaptic plasticity.By summarizing the recent discove ries on c-Abl functions,we aim to provide an overview of how its inhibition co uld be a potentially fruitful treatment to improve degenerative outcomes and delay memory loss.

Insights on the crosstalk between dendritic cells and helper T cells in novel genetic etiology for mendelian susceptible mycobacterial disease

Mendelian susceptibility to mycobacterial disease(MSMD)is an inherited predisposition to infections by Bacille-Calmette Guérin(BCG)vaccine or by environmental mycobacteria.The etiology of MSMD has been associated with up to nineteen different genetic mutations in interferon(IFN)-γ-related genes.1 Although mycobacteria susceptibility-associated genetic mutations are rare in the population,their diagnosis is crucial for an efficient and timely treatment.Kong et al.2 have recently described an autosomal recessive deficiency in the signal peptidase-like 2 A(SPPL2-a)as a new genetic etiology for MSMD in three patients that had suffered BCG dissemination disease.

Response to lipopolysaccharide in Octodon degus pups produces age-related sickness behavior but does not have effects in juveniles

During vertebrate development,the immune function is inefficient and is mainly controlled by innate defense.While there have been detailed studies of various aspects of innate immune function,the effects of this func­tion in the growth of vertebrates is still not well known.Similarly,there is little information regarding how ear­ly endotoxin exposure would affect juvenile phenotypes,specifically in a non-model mammal like a precocial rodent.We evaluated the response to an antigen and its cost in offspring of the rodent Octodon degus.We in­oculated pups at 4 different ages(8,15,22 and 30 days after birth)with an antigen to determine the ontogeny and costs of the response to an endotoxin.We assessed changes in body mass,body temperature,sickness be­havior and the levels of a key mediator of the inflammatory response,the cytokine interleukin-1β.We also de­termined the effects of early endotoxin exposure on the resting metabolic rate of juvenile animals(i.e.90 days after birth).The cytokine levels,body mass and body temperature were unaffected by time of inoculation and treatment.However,pups subjected to inoculation at 22 days after birth with the antigen showed reduced loco­motion.Juvenile resting metabolic rate was not affected by early endotoxin exposure.These results suggest that the magnitude of O.degus responses would not change with age.We discuss whether the lack of effect of the response on body mass or body condition is caused by environmental variables or by the precocial characteris­tics of O.degus.

THEMIS,the new kid on the block for T-cell development

Understanding T-cell development is a major goal of the immunology field and is crucial for the elucidation of the mechanisms behind self-tolerance and the occurrence of autoimmune disorders.T-cell development is a complex process that begins in the bone marrow or fetal liver,where lymphoid progenitors arise.