Histone acetylation is an evolutionarily conserved epigenetic mechanism of eukaryotic gene regulation which is tightly controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). In insects, life-history traits such as longevity and fecundity are severely affected by the suppression of HAT/HDAC activity, which can be achieved by RNA-mediated gene silencing or the application of chemical inhibitors. We used both experimental approaches to investigate the effect of HAT/HDAC inhibition in the pea aphid (Acyrthosiphon pisum) a model insect often used to study complex life-history traits. The silencing of HAT genes (kat6b, kat7, and kat14) promoted survival or increased the number of offspring, whereas targeting rpd3 (HDAC) reduced the number of viviparous offspring but increased the number of premature nymphs, suggesting a role in embryogenesis and eclosion. Specific chemical inhibitors of HATs/HDACs showed a remarkably severe impact on life-history traits, reducing survival, delaying development, and limiting the number of offspring. The selective inhibition of HATs and HDACs also had opposing effects on aphid body weight. The suppression of HAT/HDAC activity in aphids by RNA interference or chemical inhibition revealed similarities and differences compared to the reported role of these enzymes in other insects. Our data suggest that gene expression in A. pisum is regulated by multiple HATs/ HDACs, as indicated by the fitness costs triggered by inhibitors that suppress several of these enzymes simultaneously. Targeting multiple HATs or HDACs with combined effects on gene regulation could, therefore, be a promising approach to discover novel targets for the management of aphid pests. K E Y W O R D S acetyltransferase, deacetylase, epigenetics, life-history, RNA interference
Objectives:One-third of Parkinson’s disease (PD) patients with mild cognitive impairment (PD-MCI) convert to dementia within a few years. Markers with a high prognostic value for dementia conversion are needed. Loss of everyday function primarily caused by cognitive dysfunction is the core criterion for the diagnosis of PD dementia, with an onset of more complex instrumental activities of daily living (IADL) dysfunction in the prodromal stage. This study evaluated the phenotype associated with cognitive IADL impairment and its predictive value for defining a high-risk group for PD dementia.Methods:An observational longitudinal study using cognitive and clinical scores in addition to genetic and CSF biomarkers was conducted. The Functional Activities Questionnaire (FAQ) quotient (cut-off ≥1), indicating more cognitive than motor-driven IADL impairment, defined cognitive IADL impairment status at baseline. Hazard ratios (HR) were used to compare the impact of baseline classifications on dementia conversion.Results:Of 268 patients with PD assessed at baseline, 108 (40.3%) had PD-MCI. After a period of 3.78±0.84 years, 164 (61.2%) patients were re-assessed. At follow-up, 93 (56.7%) patients had no cognitive impairment, 54 (32.9%) fulfilled PD-MCI criteria, and 17 (10.4%) had developed dementia. The HR of baseline cognitive IADL impairment (n=37) for dementia conversion was descriptively higher than for PD-MCI, but highest in patients with both markers (HR=12.01, 95%-CI 4.47-32.22, p<0.001). In the follow-up sample, nearly half of patients (n=10, 47.6%) with baseline classification of cognitive IADL impairment and PD-MCI converted to dementia. Baseline status of cognitive IADL impairment was associated with higher non-motor burden, worse cognitive performance, and more severe IADL progression over the study period.Conclusion:The importance of differentiating between cognitive and motor aspects on ADL function in PD and monitoring cognitive ADL impairment in the prodromal stage of dementia is paramount. Patients with PD-MCI and cognitive IADL impairment may be a valuable target group for clinical trials aiming to slow down development of dementia.Trial Registration Information:ClinicalTrials.gov NCT03687203.Classification of Evidence:This study provides Class II evidence that impairment of cognitive activities of daily living is associated with progression from mild cognitive impairment to dementia among patients with Parkinson's disease.
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