Ferrari & Aprile: Lecture XXVIII Flashcards
Application of CRISPR/Cas9 Against Premature Aging Disorders
What are the hallmarks of aging?
DNA instability
telomere attrition
stem cell exhaustion
cellular senescence
epigenetic alteration
deregulation of nutrient sensing
mitochondrial dysfunction
altered intracellular communication
loss of proteostasis
What is a way to counteract aging?
use different therapies (pharmocoligical, gene editing) to target at least one of the hallmarks to revert the phenotype
What is a drug used against senescence?
Senolytic drugs
What do Senolytic drugs do?
kill senscence cell by recognizing specific features and depleting the senescence cells to avoid their accumulation
What is Hutchinson-Gilford Progeria syndrome?
rare aging disease, but one of the most studied
early onset unlike Werner
life expectancy is 14/15 years
caused by a point mutation
What kind of mutation occurs in Hutchinson-Gilford Progeria Syndrome?
silcence mutation (does not result in a different amino acid) instead it creates a cryptic splice site within exon 11 (allows for the removal of 50 amino acids and to keep the amino acid farnesylated)
What gene is affected in Hutchinson-Gilford Progeria Syndrome?
Lamin A (after post-translational modification is cleaved by the protease and the C-terminal is removed to allow the proper folding of the lamina
What do the cryptic splicing sites cause?
reduced form of the protein that has a different shape, a different folding pattern, and it is farnesylated (does not allow the proteins to cleave)
Why can children suffering from Hutchinson-Gilford Progeria Syndrome still have good cognitive ability?
Lamin is not highly expressed in the nervous system whereas instead they suffer from alopecia, atherosclerosis or osteoporosis
What kind of treatment is being used for Hutchinson-Gilford Progeria Syndrome?
pharmocological
it inhibits farnesyl-transferase to avoid post-translational modification or try to counteract mTOR signaling
*gene therapy has not been tried
