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 LmnaG609G HGPS mouse model. Collectively, the data provided here highlights NAT10 as a potential therapeutic target for HGPS.
Highlights
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
As observed in human Hutchinson Gilford Progeria Syndrome (HGPS) fibroblasts[25,26], LmnaG609G/G609G fibroblasts displayed nuclear shape defects and increased genomic instability, as reflected by a higher level of the DNA double-strand break (DSB) marker gamma H2AX, in a manner that was abrogated by Remodelin treatment (Fig. 1a, b)
The complex nature of this segmental syndrome makes it difficult to target therapeutically, with standard therapeutic approaches mainly aiming at preventing the expression or the accumulation of progerin on the nuclear envelope
Summary
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. The nuclear lamins are categorized in two distinct classes: A-type lamins (Lamin A, Lamin C, Lamin C2, and Lamin AΔ10; all encoded by the LMNA gene) and B-type lamins (Lamin B1 encoded by LMNB1, and Lamin B2 that, together with Lamin B3, are encoded by the LMNB2 gene)[4] In accord with their important roles, the loss-of-function mutations in lamin genes result in genetic syndromes with severe presentations called laminopathies (OMIM #150330; #150340; #150341). These include muscular dystrophies (for example, Emery-Dreyfus Muscular Dystrophy), peripheral neuropathies (for example, Charcot-Marie Tooth-Disease), leukodystrophy, lipodystrophy, as well as premature aging (progeria) syndromes, such as Atypical Werner Syndrome (AWS), Restrictive Dermopathy (RD), and Hutchinson Gilford Progeria Syndrome (HGPS)[2,5]. Critical for translating NAT10 inhibition toward human patients, we show that chemical or genetic targeting of NAT10 decreases the genomic instability, and improves age-related phenotypes of both homozygous and heterozygous HGPS mice
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