Ex2 L4 - Progeroid Syndromes

Question 1

What is a Progeroid Syndrome?

Answer 1

a condition in which physiological aging is mimicked in an accelerated fashion

Question 2

Progeroid indicates…

Answer 2

anything that resembles premature aging

Question 3

Progeroid syndromes occur in males and females…

Answer 3

equally

Question 4

What are the “big picture” problems in progeroid syndromes that lead to death?

Answer 4

cardiovascular problems (stroke, heart attack)

musculoskeletal (diaphragm loses function)

Question 5

What are the two ways to classify progeroid syndromes?

Answer 5

number of tissues (unimodal or segmental)

type of mutation (proteins of the nuclear envelope or DNA repair pathways)

Question 6

What are the classifications of progeroid syndromes based on number of tissues?

Answer 6

unimodal: affect one tissue only (Alzheimer’s, Parkinson’s, etc.)

segmental: affect many tissues and organ systems

Question 7

Describe the progeroid syndrome called Werner Syndrome (WS)

Answer 7

• 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

Question 8

What are some hallmarks of progeroid syndromes?

Answer 8

• telomere dysfunction
• DNA damage
• stem cell exhaustion
• cell cycle dysregulation
• senescence
• nuclear lamina alterations
• inflammation
• metabolic defects
• epigenetic changes

Question 9

What is the mutation that causes Hutchinson-Gilford Progeria Syndrome (HGPS)?

Answer 9

LMNA gene mutation (silent mutation that initiates splicing of the cleavage region)

Question 10

How do people get HGPS?

Answer 10

• de novo mutation in a germ cell or early embryo
• silent mutation - changes a nucleotide but not the amino acid

Question 11

What are clinical features of HGPS? Average age of death?

Answer 11

alopecia, atherosclerosis, lipodystrophy, myocardial infarction, and death

Average age of death: 13.5 years

Question 12

What are the molecular abnormalities caused by HGPS?

Answer 12

nuclear blebs, shortened telomeres, premature cellular senescence

Question 13

HGPS does not affect all systems because…

Answer 13

Lamin A is not abundantly expressed in all tissues (ex: nervous is unaffected, so cognition is normal)

Question 14

What is the nuclear envelope?

Answer 14

two lipid bilayers, where the inner layer is associated with the nuclear lamina

Question 15

What is the nuclear lamina?

Answer 15

• contains intermediate filaments and proteins
• provides structural support, organizes chromatin, regulates DNA replication, and anchors nuclear pores

Question 16

What is the normal process of Lamin A getting into the nucleus?

Answer 16

• 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

Question 17

What is a farnesyl?

Answer 17

a large hydrophobic moiety that helps target lamin A to the nuclear lamina

Question 18

Describe the mechanism of how the HGPS mutation causes the disease

Answer 18

• 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

Question 19

What is Lonafarnib?

Answer 19

• 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)

Question 20

Lonafarnib was originally developed as…

Answer 20

as a therapeutic for head and neck cancer

Question 21

When Lonafarnib was used on progeria skin cells, what happened?

Answer 21

Nuclear blebbing was gone within a couple hours

Question 22

What is HGPS?

Answer 22

Hutchinson-Gilford Progeria Syndrome
- mostly prevalent and widely studied progeroid syndrome