Fisher, P. | Search bioRxiv

bioRxiv2019

Misfolded α-synuclein causes hyperactive respiration without functional deficit in live neuronal cells

The misfolding and aggregation of the largely disordered protein, -synuclein, is a central pathogenic event that occurs in the synucleinopathies; a group of neurodegenerative disorders that includes Parkinsons disease. While there is a clear link between protein misfolding and neuronal vulnerability, the precise pathogenic mechanisms employed by disease-associated -synuclein are unresolved. Here, we studied the pathogenicity of misfolded -synuclein produced using the Protein Misfolding Cyclic Amplification (PMCA) assay. To do this, previous published methods were adapted to allow PMCA-induced protein fibrillization to occur under non-toxic conditions. Insight into potential intracellular targets of misfolded -synuclein was obtained using an unbiased lipid screen of 15 biologically relevant lipids that identified cardiolipin (CA) as a potential binding partner for PMCA-generated misfolded -synuclein. To investigate if such an interaction can impact the properties of -synuclein misfolding, protein fibrillization was carried out in the presence of the lipid. We show CA both accelerates the rate of -synuclein fibrillization and produces species that harbour enhanced resistance to proteolysis. Because CA is virtually exclusively expressed in the inner mitochondrial membrane, we then assessed the ability of these misfolded species to alter mitochondrial respiration in live non-transgenic SH-SY5Y neuroblastoma cells. Extensive analysis revealed misfolded -synuclein causes hyperactive mitochondrial respiration without causing any functional deficit. These data give strong support for the mitochondrion as a target for misfolded -synuclein and reveals persistent, hyperactive respiration as a potential up-stream pathogenic event associated with the synucleinopathies. Summary statementMisfolded -synuclein that was produced using the Protein Misfolding Cyclic Amplification (PMCA) assay was found to associate with cardiolipin and cause hyperactive respiration in neuronal cells.

neuroscience↗

bioRxiv2019

Gut feelings begin in childhood: how the gut metagenome links to early environment, caregiving, and behavior

Psychosocial environments impact normative behavioral development in children, increasing the risk of problem behaviors and psychiatric disorders across the lifespan. Converging evidence demonstrates early normative development is affected by the gut microbiome, which itself can be altered by early psychosocial environments. Nevertheless, these relationships are poorly understood in childhood, particularly beyond peri- and postnatal microbial colonization. To determine the gut microbiomes role in the associations between childhood adversity and behavioral development, we conducted a metagenomic investigation among cross-sectional sample of early school-aged children with a range of adverse experiences and caregiver stressors and relationships. Our results indicate that the taxonomic and functional composition of the gut microbiome links to behavioral dysregulation during a critical period of child development. Furthermore, our analysis reveals that both socioeconomic risk exposure and child behaviors associate with the relative abundances of specific taxa (e.g., Bacteroides and Bifidobacterium species) as well as functional modules encoded in their genomes (e.g., monoamine metabolism) that have been linked to cognition and health. We also identified heretofore novel linkages between gut microbiota, their functions, and behavior. These findings hold important translational implications for developmental psychology and microbiome sciences alike, as they suggest that caregiver behavior might mitigate the impact of socioeconomic risk on the microbiome and modify the relationship between subclinical symptoms of behavioral dysregulation and the gut microbiome in early school-aged children.

microbiology↗