ABSTRACT
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, but devastating genetic disease characterized by segmental premature aging, with cardiovascular disease being the main cause of death. Cells from HGPS patients accumulate progerin, a permanently farnesylated, toxic form of Lamin A, disrupting the nuclear shape and chromatin organization, leading to DNA-damage accumulation and senescence. Therapeutic approaches targeting farnesylation or aiming to reduce progerin levels have provided only partial health improvements. Recently, we identified Remodelin, a small-molecule agent that leads to amelioration of HGPS cellular defects through inhibition of the enzyme N-acetyltransferase 10 (NAT10). Here, we show the preclinical data demonstrating that targeting NAT10 in vivo, either via chemical inhibition or genetic depletion, significantly enhances the healthspan in a Lmna G609G HGPS mouse model. Collectively, the data provided here highlights NAT10 as a potential therapeutic target for HGPS.
Subject(s)
Aging, Premature/drug therapy , Genomic Instability/drug effects , Hydrazones/pharmacology , N-Terminal Acetyltransferase A/antagonists & inhibitors , Progeria/drug therapy , Thiazoles/pharmacology , Aging, Premature/genetics , Aging, Premature/mortality , Aging, Premature/pathology , Animals , DNA Damage/drug effects , DNA Damage/genetics , Disease Models, Animal , Female , Genomic Instability/genetics , Humans , Hydrazones/therapeutic use , Kaplan-Meier Estimate , Lamin Type A/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , N-Terminal Acetyltransferase A/genetics , N-Terminal Acetyltransferase A/metabolism , N-Terminal Acetyltransferases , Progeria/genetics , Progeria/mortality , Progeria/pathology , Thiazoles/therapeutic useABSTRACT
The mouse olfactory sensory neuron (OSN) repertoire is composed of 10 million cells and each expresses one olfactory receptor (OR) gene from a pool of over 1000. Thus, the nose is sub-stratified into more than a thousand OSN subtypes. Here, we employ and validate an RNA-sequencing-based method to quantify the abundance of all OSN subtypes in parallel, and investigate the genetic and environmental factors that contribute to neuronal diversity. We find that the OSN subtype distribution is stereotyped in genetically identical mice, but varies extensively between different strains. Further, we identify cis-acting genetic variation as the greatest component influencing OSN composition and demonstrate independence from OR function. However, we show that olfactory stimulation with particular odorants results in modulation of dozens of OSN subtypes in a subtle but reproducible, specific and time-dependent manner. Together, these mechanisms generate a highly individualized olfactory sensory system by promoting neuronal diversity.
Subject(s)
Genetic Variation , Olfactory Pathways/physiology , Olfactory Receptor Neurons/classification , Receptors, Odorant/genetics , Animals , Gene Expression Profiling , Mice , Olfactory Receptor Neurons/physiology , Sequence Analysis, RNAABSTRACT
Use of voice output communication aids (VOCAs) can be a very effective strategy to assist people with speech impairments in communicating. Despite this, people who use communication aids often express frustration with VOCAs-desiring devices that are simpler, quicker and more effective to use. Whilst it is not possible to resolve all these issues with technology, it is argued that significant progress can be made. The use of contextual information is one development that could improve the simplicity and effectiveness of communication aid design. Improving the effectiveness of communication aids, including through the use of context support, is a goal of the NIHR Devices for Dignity Assistive Technology Theme. This discussion paper examines the potential for creating 'context aware' communication aids. Three projects in which the authors have been involved are described to illustrate different approaches to the use of contextual information.
