Revisiting the difference between instrumental and terminal values to predict (stimulating) prosocial behaviours: the transcendental‐change profile

Past research suggests that the connection between values and people's behaviour may not be as straightforward and robust as has been claimed. We propose that a more holistic and discriminative view that acknowledges the influence of a specific combination of values on specific kinds of behaviour is needed. In the current project, we test two hypotheses regarding the transcendental-change profile (TCP). First, that TCP is characterized by a combination of the readiness to engage in those challenges (instrumental) that can make the world a better place (terminal). Second, the centrality of the TCP facilitates performance of those prosocial actions that are perceived as stimulating and global. The results of five studies support the reliability and validity of this conceptualization of TCP (Studies 1 and 2), and show that when the prosocial initiative is perceived as either global (Study 3) or stimulating (Studies 4 and 5), the TCP is the strongest predictor of the willingness and commitment to engage in such prosocial action.info:eu-repo/semantics/acceptedVersio

Targeting autophagy in neurodegenerative diseases

© 2014 Elsevier B.V. All rights reserved. The most prevalent neurodegenerative disorders involve protein misfolding and the aggregation of specific proteins. Autophagy is becoming an attractive target to treat neurodegenerative disorders through the selective degradation of abnormally folded proteins by the lysosomal pathway. However, accumulating evidence indicates that autophagy impairment at different regulatory steps may contribute to the neurodegenerative process. Thus, a complex scenario is emerging where autophagy may play a dual role in neurodegenerative diseases by causing the downstream effect of promoting the degradation of misfolded proteins and an upstream effect where its deregulation perturbs global proteostasis, contributing to disease progression. Challenges in the future development of therapeutic strategies to target the autophagy pathway are discussed

ER chaperones in neurodegenerative disease: Folding and beyond

Proteins along the secretory pathway are co-translationally translocated into the lumen of the endoplasmic reticulum (ER) as unfolded polypeptide chains. Afterwards, they are usually modified with N-linked glycans, correctly folded and stabilized by disulfide bonds. ER chaperones and folding enzymes control these processes. The accumulation of unfolded proteins in the ER activates a signaling response, termed the unfolded protein response (UPR). The hallmark of this response is the coordinated transcriptional up-regulation of ER chaperones and folding enzymes. In order to discuss the importance of the proper folding of certain substrates we will address the role of ER chaperones in normal physiological conditions and examine different aspects of its contribution in neurodegenerative diseaseFONDECYT 1150608 3150097 1161284 CONICYT Millennium Institute P09-015-F FONDAP 1515001

Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis

Abstract Background Amyotrophic lateral sclerosis (ALS) is a multifactorial fatal motoneuron disease without a cure. Ten percent of ALS cases can be pointed to a clear genetic cause, while the remaining 90% is classified as sporadic. Our study was aimed to uncover new connections within the ALS network through a bioinformatic approach, by which we identified C13orf18, recently named Pacer, as a new component of the autophagic machinery and potentially involved in ALS pathogenesis. Methods Initially, we identified Pacer using a network-based bioinformatic analysis. Expression of Pacer was then investigated in vivo using spinal cord tissue from two ALS mouse models (SOD1G93A and TDP43A315T) and sporadic ALS patients. Mechanistic studies were performed in cell culture using the mouse motoneuron cell line NSC34. Loss of function of Pacer was achieved by knockdown using short-hairpin constructs. The effect of Pacer repression was investigated in the context of autophagy, SOD1 aggregation, and neuronal death. Results Using an unbiased network-based approach, we integrated all available ALS data to identify new functional interactions involved in ALS pathogenesis. We found that Pacer associates to an ALS-specific subnetwork composed of components of the autophagy pathway, one of the main cellular processes affected in the disease. Interestingly, we found that Pacer levels are significantly reduced in spinal cord tissue from sporadic ALS patients and in tissues from two ALS mouse models. In vitro, Pacer deficiency lead to impaired autophagy and accumulation of ALS-associated protein aggregates, which correlated with the induction of cell death. Conclusions This study, therefore, identifies Pacer as a new regulator of proteostasis associated with ALS pathology