Biology subjects

Castro, S. L.

Publications and source records attributed to Castro, S. L..

4 recordsLinked to original sources

bioRxiv2021

Neuronal NADPH oxidase in Parkinson disease pathogenesis

Mitochondrial dysfunction and oxidative stress are strongly implicated in the pathogenesis of Parkinsons disease (PD) and there is evidence that mitochondrially-generated superoxide can activate NADPH oxidase 2 (NOX2), which is a major enzymatic generator of superoxide. Although NOX2 has been examined in the context of PD, previous studies have focused on microglial function; the role of neuronal NOX2 in PD pathogenesis remains to be defined. Here we devised and validated a proximity ligation assay for NOX2 activity and demonstrated that in human PD and 2 models thereof, neuronal NOX2 is highly active in substantia nigra dopamine neurons. Further, NOX2 activity is responsible for accumulation, post-translational modification and oligomerization of -synuclein as well as activation of leucine-rich repeat kinase 2 (LRRK2). Administration of a brain-penetrant, specific NOX2 inhibitor prevented NOX2 activation and its downstream effects in vivo in a rat model of PD. We conclude that neuronal NOX2 is a major contributor to oxidative stress in PD, to -synuclein pathology and to LRRK2 activation in idiopathic PD. In this context, NOX2 inhibitors hold potential as a disease-modifying therapy in PD. SummaryIn dopamine neuron, NADPH oxidase isoform 2 amplifies the oxidative stress-related pathogenic cascade in Parkinsons disease

neuroscience↗

bioRxiv2021

Associations Between Vocal Emotion Recognition and Socio-emotional Adjustment in Children

The human voice is a primary channel for emotional communication. It is often presumed that being able to recognise vocal emotions is important for everyday socio-emotional functioning, but direct empirical evidence for this remains scarce. Here, we examined relationships between vocal emotion recognition and socio-emotional adjustment in children. The sample included 6 to 8-year-old children (N = 141). The emotion tasks required them to categorise five emotions conveyed by nonverbal vocalisations (e.g., laughter, crying) and speech prosody: anger, disgust, fear, happiness, sadness, plus neutrality. Socio-emotional adjustment was independently evaluated by the childrens teachers using a multi-dimensional questionnaire of self-regulation and social behaviour. Based on frequentist and Bayesian analyses, we found that higher emotion recognition in speech prosody related to better general socio-emotional adjustment. This association remained significant even after accounting for the childrens general cognitive ability, age, sex, and parental education in multiple regressions. Follow-up analyses indicated that the advantages were particularly robust for the socio-emotional dimensions prosocial behaviour and cognitive and behavioural self-regulation. For emotion recognition in nonverbal vocalisations, no associations with socio-emotional adjustment were found. Overall, these results support the close link between childrens emotional prosody recognition skills and their everyday social behaviour.

neuroscience↗

bioRxiv2020

The industrial solvent trichloroethylene induces LRRK2 kinase activity and dopaminergic neurodegeneration in a rat model of Parkinson's disease

Gene-environment interaction is implicated in the majority of idiopathic Parkinsons disease (PD) risk, and some of the most widespread environmental contaminants are selectively toxic to dopaminergic neurons. Pesticides have long been connected to PD incidence, however, it has become increasingly apparent that other industrial byproducts likely influence neurodegeneration. For example, organic solvents, which are used in chemical, machining, and dry-cleaning industries, are of growing concern, as decades of solvent use and their effluence into the environment has contaminated much of the worlds groundwater and soil. Like some pesticides, certain organic solvents, such as the chlorinated halocarbon trichloroethylene (TCE), are mitochondrial toxicants, which are collectively implicated in the pathogenesis of dopaminergic neurodegeneration. Recently, we hypothesized a possible gene-environment interaction may occur between environmental mitochondrial toxicants and the protein kinase LRRK2, mutations of which are the most common genetic cause of familial and sporadic PD. In addition, emerging data suggests that elevated wildtype LRRK2 kinase activity also contributes to the pathogenesis of idiopathic PD. To this end, we investigated whether chronic, systemic TCE exposure (200 mg/kg) in aged rats produced wildtype LRRK2 activation and influenced predegenerative dopaminergic dysfunction. Interestingly, we found that TCE not only induced LRRK2 kinase activity in the brain, but produced a significant dopaminergic lesion in the nigrostriatal tract, elevated oxidative stress, and caused endolysosomal dysfunction and protein accumulation (-synuclein). Together, these data suggest that TCE-induced LRRK2 kinase activity contributed to the selective toxicity of dopaminergic neurons. We conclude that gene-environment interactions between certain industrial contaminants and LRRK2 likely influence PD risk.

pharmacology and toxicology↗

bioRxiv2020

Disulfide bridge formation prevents CaMKII/Calmodulin interaction in Parkinson's disease

There is increasing evidence for disordered Ca2+ signaling in dopamine neurons in Parkinsons disease (PD), and this likely involves altered Ca2+/calmodulin-dependent protein kinase II (CaMKII) function. Previous work suggests that oxidative stress - a major feature in PD pathogenesis - affects regulatory methionine residues that sustain CaMKII activity in a Ca2+/CaM-independent manner. Here, applying computational modeling, we predicted formation of a defined disulfide bridge close to the CaMKII docking site for Ca2+/CaM binding. In vitro and in vivo investigations using PD models revealed formation of a disulfide bridge and loss of the CaMKII-calmodulin interaction. Mutagenesis of the relevant cysteine residues abrogated disulfide bridge formation and recovered the CaMKII-calmodulin interaction. Importantly, dopamine neurons from post-mortem PD brain specimens also lost this regulatory protein-protein interaction, providing relevance in the human disease. This study provides novel insights into oxidative CaMKII-CaM dysfunction, which may contribute to the pathophysiology of PD.

neuroscience↗