Ex2 L4 - Progeroid Syndromes Flashcards
What is a Progeroid Syndrome?
a condition in which physiological aging is mimicked in an accelerated fashion
Progeroid indicates…
anything that resembles premature aging
Progeroid syndromes occur in males and females…
equally
What are the “big picture” problems in progeroid syndromes that lead to death?
cardiovascular problems (stroke, heart attack)
musculoskeletal (diaphragm loses function)
What are the two ways to classify progeroid syndromes?
number of tissues (unimodal or segmental)
type of mutation (proteins of the nuclear envelope or DNA repair pathways)
What are the classifications of progeroid syndromes based on number of tissues?
unimodal: affect one tissue only (Alzheimer’s, Parkinson’s, etc.)
segmental: affect many tissues and organ systems
Describe the progeroid syndrome called Werner Syndrome (WS)
- mutation of the WRN gene that encodes helicase
- causes issues LATER in life because damages have to accumulate over time
- recessive
- more likely to get cancer
What are some hallmarks of progeroid syndromes?
- telomere dysfunction
- DNA damage
- stem cell exhaustion
- cell cycle dysregulation
- senescence
- nuclear lamina alterations
- inflammation
- metabolic defects
- epigenetic changes
What is the mutation that causes Hutchinson-Gilford Progeria Syndrome (HGPS)?
LMNA gene mutation (silent mutation that initiates splicing of the cleavage region)
How do people get HGPS?
- de novo mutation in a germ cell or early embryo
- silent mutation - changes a nucleotide but not the amino acid
What are clinical features of HGPS? Average age of death?
alopecia, atherosclerosis, lipodystrophy, myocardial infarction, and death
Average age of death: 13.5 years
What are the molecular abnormalities caused by HGPS?
nuclear blebs, shortened telomeres, premature cellular senescence
HGPS does not affect all systems because…
Lamin A is not abundantly expressed in all tissues (ex: nervous is unaffected, so cognition is normal)
What is the nuclear envelope?
two lipid bilayers, where the inner layer is associated with the nuclear lamina
What is the nuclear lamina?
- contains intermediate filaments and proteins
- provides structural support, organizes chromatin, regulates DNA replication, and anchors nuclear pores
What is the normal process of Lamin A getting into the nucleus?
- Lamin A is farnesylated, which targets it to the nuclear lamina
- once it gets there, the farnesyl is cleaved at the RSYLLG site
- this leaves us with Mature Lamin A
What is a farnesyl?
a large hydrophobic moiety that helps target lamin A to the nuclear lamina
Describe the mechanism of how the HGPS mutation causes the disease
- the HGPS silent mutation produces the same amino acid, but initates a splice sequence
- the splice deletes 50 amino acids, including the RSYLLG cleavage site to remove the farnesyl
- when the farnesylated Lamin A (aka Progerin) reaches the lamina, there is no cleavage site, so the farnesyl remains attached
- therefore, it remains Lamin A + farnesly = Progerin, and progerin builds up causing nuclear blebbing
What is Lonafarnib?
- acts as a farnesyl transferase inhibitor (FTI)
- prevents farnesylation of Lamin A and therefore prevent the buildup of progerin proteins
- also stops Lamin A from getting to the lamina, but that’s ok, because:
– other Lamins are there too, so we can stop the entire pathway
–the body compensates by using another mechanism to get it there (which causes other problems that scientists are trying to solve with another medication)
Lonafarnib was originally developed as…
as a therapeutic for head and neck cancer
When Lonafarnib was used on progeria skin cells, what happened?
Nuclear blebbing was gone within a couple hours
What is HGPS?
Hutchinson-Gilford Progeria Syndrome
- mostly prevalent and widely studied progeroid syndrome
