Progeria

Segmental diseases: DNA damage, immunoclearance? & nuclear lamina defects…?

• 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

—> Lamin C only mice show extended lifespan

Progerin lacks 150 nucleotides (50 amino acids) that contain azmpste24 cleavage site

—> Increased Amounts of Progerin Protein at Old Age

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

• 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

• Transcription and Translation

• Ubiquitin-ProteasomeSystem (UPS)

• Endo-Lysosomal Trafficking

• 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?