Relationship Repair After Infidelity: Looking at Other Perspectives

Prior research examining relationship repair after infidelity scenarios tends to focus primarily on heterosexual relationships, and often does not take into consideration the nuance between emotional and sexual infidelity, which, according to evolutionary psychology theories, tends to be salient to individuals based on their reproductive challenges. This research intended to rectify that dearth, hypothesizing that non-heterosexual participants would be more likely to repair a relationship where a partner has committed sexual infidelity than they would be to repair a relationship where a partner has committed an emotional infidelity. As well, based on prior research, there were expectations for sex differences in the likelihood of repairing a relationship after infidelity by a partner for participants in committed relationships, with female participants likely to repair emotional infidelity and male participants likely to repair sexual infidelity. In a survey of volunteers online, likelihood of repair for relationships after sexual or emotional infidelity was related to the sexual orientation of participants. Homosexual/other individuals were equally likely to repair their relationship after an emotional or sexual infidelity was committed by a partner and were more likely to repair a relationship after a partner committed a sexual infidelity than heterosexual individuals were. A qualitative question component obtained more information about the participants¿ logic behind their reconciliation choices, and these results along with the quantitative results are discussed and interpreted using themes from earlier research

Understanding the Interaction between LRRK2 and PINK1: Implications for Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects nearly 1% of the US population over the age of 65. While PD is primarily a sporadic disease, roughly 10% of PD cases are due to genetic mutations, giving rise to familial forms of PD. Interestingly, mutations in two kinases, the leucine-rich repeat kinase 2 (LRRK2) and the PTEN-induced kinase 1 (PINK1), underlie two forms familial PD. Although the pathogenic mechanisms still remain unknown, many insights have been gained from investigating toxin insults and genetic mutations that cause parkinsonian phenotypes. Studies using neurotoxins and genetic mutations that underlie familial PD have implicated mitochondrial dysfunction in the pathogenesis of PD. This project sought to identify modes of neuroprotection that ameliorated the effects of LRRK2 mutations on neuronal and mitochondrial homeostasis. The mechanism of protein kinase A (PKA)-mediated neuroprotection was investigated in neurotoxin and genetic models of PD. This study also explored the mechanisms of PINK1-mediated neuroprotection. Activation of PKA prevented mutant LRRK2-induced neurite shortening by suppressing autophagy through the phosphorylation of the autophagy protein, the microtubule-associated protein light chain 3. This study also found that mutant LRRK2 causes mitochondrial degradation by autophagy in the dendrites of neurons, which led to shortening of the dendrites. PINK1 suppressed the autophagy induction elicited by mutant LRRK2 and prevented the mitochondrial degradation and neurite shortening. Furthermore, mutant LRRK2 caused a delay in calcium clearance after neuronal iv depolarization. This prolonged elevation in intracellular calcium caused mitochondrial depolarization followed by degradation. Indeed, calcium chelation or inhibition of voltage-gated calcium channel restored calcium homeostasis and attenuated the mitochondrial degradation and dendrite shortening induced by LRRK2 mutations. Finally using immunoprecipitation and 2- dimensional gel electrophoresis, PINK1 was found to interact with and regulate the phosphorylation status of proteins that maintain mitochondrial polarization, energy production, and calcium buffering. Overall, these results indicate that autophagy modulation and restoration of mitochondrial homeostasis protects against mutant LRRK2. This study proposes that calcium imbalance, mitochondrial dysfunction, and autophagy dysregulation are early events in the pathogenesis of familial and sporadic PD and thus, are potential therapeutic targets for PD

Casting the autophagy net

Two studies investigate how cells regulate the formation of autophagosomes

Interactions between Ras and Rap signaling pathways during neurodevelopment in health and disease

The Ras family of small GTPases coordinates tissue development by modulating cell proliferation, cell-cell adhesion, and cellular morphology. Perturbations of any of these key steps alter nervous system development and are associated with neurological disorders. While the underlying causes are not known, genetic mutations in Ras and Rap GTPase signaling pathways have been identified in numerous neurodevelopmental disorders, including autism spectrum, neurofibromatosis, intellectual disability, epilepsy, and schizophrenia. Despite diverse clinical presentations, intersections between these two signaling pathways may provide a better understanding of how deviations in neurodevelopment give rise to neurological disorders. In this review, we focus on presynaptic and postsynaptic functions of Ras and Rap GTPases. We highlight various roles of these small GTPases during synapse formation and plasticity. Based on genomic analyses, we discuss how disease-related mutations in Ras and Rap signaling proteins may underlie human disorders. Finally, we discuss how recent observations have identified molecular interactions between these pathways and how these findings may provide insights into the mechanisms that underlie neurodevelopmental disorders

Expanded genetic screening in Caenorhabditis elegans identifies new regulators and an inhibitory role for NAD+ in axon regeneration.

The mechanisms underlying axon regeneration in mature neurons are relevant to the understanding of normal nervous system maintenance and for developing therapeutic strategies for injury. Here, we report novel pathways in axon regeneration, identified by extending our previous function-based screen using the C. elegans mechanosensory neuron axotomy model. We identify an unexpected role of the nicotinamide adenine dinucleotide (NAD+) synthesizing enzyme, NMAT-2/NMNAT, in axon regeneration. NMAT-2 inhibits axon regrowth via cell-autonomous and non-autonomous mechanisms. NMAT-2 enzymatic activity is required to repress regrowth. Further, we find differential requirements for proteins in membrane contact site, components and regulators of the extracellular matrix, membrane trafficking, microtubule and actin cytoskeleton, the conserved Kelch-domain protein IVNS-1, and the orphan transporter MFSD-6 in axon regrowth. Identification of these new pathways expands our understanding of the molecular basis of axonal injury response and regeneration

PKA Phosphorylation of NCLX Reverses Mitochondrial Calcium Overload and Depolarization, Promoting Survival of PINK1-Deficient Dopaminergic Neurons

Mitochondrial Ca2+ overload is a critical, preceding event in neuronal damage encountered during neurodegenerative and ischemic insults. We found that loss of PTEN-induced putative kinase 1 (PINK1) function, implicated in Parkinson disease, inhibits the mitochondrial Na+/Ca2+ exchanger (NCLX), leading to impaired mitochondrial Ca2+ extrusion. NCLX activity was, however, fully rescued by activation of the protein kinase A (PKA) pathway. We further show that PKA rescues NCLX activity by phosphorylating serine 258, a putative regulatory NCLX site. Remarkably, a constitutively active phosphomimetic mutant of NCLX (NCLXS258D) prevents mitochondrial Ca2+ overload and mitochondrial depolarization in PINK1 knockout neurons, thereby enhancing neuronal survival. Our results identify an mitochondrial Ca2+ transport regulatory pathway that protects against mitochondrial Ca2+ overload. Because mitochondrial Ca2+ dyshomeostasis is a prominent feature of multiple disorders, the link between NCLX and PKA may offer a therapeutic target

Expanded Genetic Screening in \u3cem\u3eCaenorhabditis elegans\u3c/em\u3e Identifies New Regulators and an Inhibitory Role for NAD\u3csup\u3e+\u3c/sup\u3e in Axon Regeneration

The mechanisms underlying axon regeneration in mature neurons are relevant to the understanding of normal nervous system maintenance and for developing therapeutic strategies for injury. Here, we report novel pathways in axon regeneration, identified by extending our previous function-based screen using the C. elegans mechanosensory neuron axotomy model. We identify an unexpected role of the nicotinamide adenine dinucleotide (NAD+) synthesizing enzyme, NMAT-2/NMNAT, in axon regeneration. NMAT-2 inhibits axon regrowth via cell-autonomous and non-autonomous mechanisms. NMAT-2 enzymatic activity is required to repress regrowth. Further, we find differential requirements for proteins in membrane contact site, components and regulators of the extracellular matrix, membrane trafficking, microtubule and actin cytoskeleton, the conserved Kelch-domain protein IVNS-1, and the orphan transporter MFSD-6 in axon regrowth. Identification of these new pathways expands our understanding of the molecular basis of axonal injury response and regeneration

Regulation of the autophagy protein LC3 by phosphorylation

PKA puts the brakes on autophagy by inhibiting LC3 recruitment to autophagosomes

Post‐translationally‐modified structures in the autophagy machinery: an integrative perspective

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/113777/1/febs13356_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/113777/2/febs13356.pd