A Classification of Aging Diseases
Segmental diseases: DNA damage, immunoclearance? & nuclear lamina defects…?
Systemic Defects in DNA Damage vs Nuclear Lamina Segmental Progeroid Diseases
Hutchinson-Gilford Progeria Syndrome (HGPS)
The gene defect that causes HGPS
Nuclear membrane, Nuclear Envelope and Nuclear Lamina
Nuclear Lamina form Higher Order Structures that Protect Nuclear Integrity
Nuclear lamina are important for NPC organization and functioning
The nuclear lamina are important for chromatin organization & gene expression
The nuclear lamina are important for telomere organization
LMNA gene alternative splicing
—> Lamin C only mice show extended lifespan
Progerin
Progerin lacks 150 nucleotides (50 amino acids) that contain azmpste24 cleavage site
—> Increased Amounts of Progerin Protein at Old Age
Protein Processing
Lamin A and Progerin, but not lamin C, get farnesylated
—> FTI treatment ameliorates HGPS patient cells ageing phenotype
—> FTI treatment rescues accelerated aging in HGPS mouse model
—> Mouse model that expresses non-farnesylated progerin does not prematurely age
Effects of HGPS mutation on cellular homeostasis
Progerin disrupts interstitial t-loops (ITL) at telomeres
Progerin causes decreased efficiency of DNA repair pathways
Progerin increases Senescence Associated Secretory Phenotype (SASP)
Progerin causes a global loss of heterochromatin, and derepression of certain genes
Progerin increases stalled replication forks, and mislocalization ofNER associated XPA at stalled replication forks
Increased amounts of cytosolic DNA trigger inflammation through cGAS-STING pathway
3 crucial drivers of aging
Transcription and Translation
Ubiquitin-ProteasomeSystem (UPS)
Endo-Lysosomal Trafficking
Therapeutic treatments
Farnesyl Transferase Inhibitor
Anti-Sense Oligo (ASO) Therapies to modulate lamin A/Progerin splicing
CRISPR-Cas9 based Gene Editing Strategies: Correct the 1824 C>T mutation?
Last changed2 years ago