Biology subjects

Mustafa, R.

Publications and source records attributed to Mustafa, R..

3 recordsLinked to original sources

bioRxiv2024

Subjective salience ratings are a reliable proxy for physiological measures of arousal

Pain is an inherently salient multidimensional experience that signals potential bodily threats and promotes nocifensive behaviours. Any stimulus can be salient depending on its features and context. This poses a challenge in delineating pain-specific processes in the brain, rather than salience-driven activity. It is thus essential to salience match control (innocuous) stimuli and noxious stimuli, to remove salience effects, when aiming to delineate pain-specific mechanisms. Previous studies have salience-matched either through subjective salience ratings or the skin conductance response (SCR). The construct of salience is not intuitive, and thus matching through self-report poses challenges. SCR is used as a proxy measure that captures physiological arousal, which overcomes the nebulous construct of salience. However, SCR cannot be used to salience-match in real-time (i.e., during an experiment) and assumes an association between salience and physiological arousal elicited by painful and non-painful stimuli, but this has not been explicitly tested. To determine whether salience and physiological arousal are associated, thirty-five healthy adults experienced 30 heat pain and 30 non-painful electric stimuli of varying intensities. Stimuli were subjectively matched for salience and SCR was measured to each presentation. A linear mixed model found no differences in SCR between salience-matched heat and electric stimuli. A mediation analysis showed that salience fully mediated the relationship between stimulus intensity and SCR (proportion mediated=83%). In conclusion, salience and physiological arousal are associated, and subjective salience ratings are a suitable for salience-matching pain with non-painful stimuli. Future work can thus use subjective salience ratings to delineate pain-specific processes.

neuroscience↗

bioRxiv2023

Evidence for Involvement of WDPCP Gene in Alcohol Consumption, Lipid Metabolism, and Liver Cirrhosis

Alcohol consumption continues to cause a significant health burden globally. The advent of genome-wide association studies has unraveled many genetic loci associated with alcohol consumption. However, the biological effect of these loci and the pathways involved in alcohol consumption and its health consequences such as alcohol liver disease (ALD) remain to be elucidated. We combined human studies with model organisms Drosophila melanogaster and Caenorhabditis elegans to shed light on the molecular mechanisms underlying alcohol consumption and the health outcomes caused by alcohol intake. Using genetics and metabolite data within the Airwave study, a sample of police forces in the UK, we performed several analyses to identify changes in circulating metabolites that are triggered by alcohol consumption. We selected a set of genes annotated to genetic variants that are (1) known to be implicated in alcohol consumption, (2) are linked to liver function, and (3) are associated with expression (cis-eQTL) of their annotated genes. We used mutations and/or RNA interference (RNAi) to suppress the expression of these genes in C. elegans and Drosophila. We examined the effect of this suppression on ethanol consumption and on the sedative effects of ethanol. We also investigated the alcohol-induced changes in triacylglycerol (TGA) levels in Drosophila and tested differences in locomotion of C. elegans after acute exposure to ethanol. In human population, we found an enrichment of the alcohol-associated metabolites within the linoleic acid (LNA) and alpha linolenic acid (ALA) metabolism pathway. We further showed the effect of ACTR1B and MAPT on locomotion in C. elegans after exposure to ethanol. We demonstrated that three genes namely WDPCP, TENM2 and GPN1 modify TAG levels in Drosophila. Finally, we showed that gene expression of WDPCP in human population is linked to liver fibrosis and liver cirrhosis. Our results underline the impact of alcohol consumption on metabolism of lipids and pinpoints WDPCP as a gene with potential impact on fat accumulation upon exposure to ethanol suggesting a possible pathway to ALD.

genetics↗

bioRxiv2021

Nucleolar stress controls mutant Huntingtin toxicity and monitors Huntington disease progression

Transcriptional and cellular stress surveillance deficits are hallmarks of Huntingtons disease (HD), a fatal autosomal dominant neurodegenerative disorder, caused by a pathological expansion of CAG repeats in the Huntingtin (HTT) gene. The nucleolus, a dynamic nuclear biomolecular condensate and the site of ribosomal RNA (rRNA) transcription, is implicated in the cellular stress response and in protein quality control. While the exact pathomechanisms of HD remain unclear, the impact of nucleolar dysfunction on HD pathophysiology in vivo is elusive. Here we identified aberrant maturation of rRNA and decreased translational rate in association with human mutant Huntingtin (mHTT) expression. Genetic disruption of nucleolar integrity in vulnerable striatal neurons of the R6/2 HD mouse model decreases mHTT disperse state in the nucleus, exacerbating the motor deficits. The protein nucleophosmin 1 (NPM1), important for nucleolar integrity and rRNA maturation, loses its nucleolar localization. NPM1 de-localization occurs in the striatum and in the skeletal muscle of the progressive zQ175 knock-in HD mouse model, mimicking the phenotype of HD patients in skeletal muscle biopsies. Taken together, we showed that nucleolar integrity regulates the formation of mHTT inclusions in vivo, and identified NPM1 as a novel, readily detectable peripheral histopathological marker of HD progression.

neuroscience↗