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The Young Who Die Old:
Understanding The Premature Aging
Disease Progeria and its Link to
Normal Aging
Susan Michaelis, Ph.D.
JHMI Science Writers’ Boot Camp
May 7, 2018
One common view of aging: A gradual general decline of multiple cellular systems in our bodies
1975
1978
20012006
2011 2014 2017
Nicholas Nixon
Brown Sisters
The Premature Aging Disease Hutchinson Gilford Progeria Syndrome
(HGPS, progeria) Suggests a more nuanced view:
Alterations in particular pathways can change the rate of aging
Early onset diseases can point to particularly vulnerable components in a system
S
C
O-CH3
ZMPSTE24
Prelamin A
MatureLamin A
A to Z:Lamin A cleavage
by the ZMPSTE24 protease
ZMPSTE24 cleavage is critical for health
farnesyl
Wild-type
Lamin A
HGPS-O-CH3
S
CMutant Lamin A
Defective lamin A processing results in the premature aging disease
HGPS
Sam Sam’s Mom
ZMPSTE24
Sam Berns TEDx talk 2013“My Philosophy for a Happy Life”
>29 million views
Mutations either in Lamin A or ZMPSTE24 cause related progeroid diseases
A• Structural scaffold for the nuclear envelope
• Interact with DNA, regulates gene expression
Lamin A WT
progeria
S
C
O-CH3
S
C
O-CH3
ZMPSTE24
Early on- there was no connection between lamin A, ZMPSTE24, and progeria
HGPS
Rare disease (1 in 4 million) Accelerated aging: • Thin skin• Growth failure• Loss of body fat, hair• Joint and bone defects• Blood vessel defect-
early onset atherosclerosis
The key advance: HGPS maps to the LMNA gene encoding Lamin A (F. Collins and N. Levy labs, 2003)
Fatal (death ~age 13) from heart attack or stroke
Brought disparate fields together and galvanized progress
First described by Dr. Jonathan Hutchinson (1886) and Dr. Hastings Gilford (1897)
S
C
O-CH3
ZMPSTE24
Prelamin A
MatureLamin A
*
Hypothesis: farnesyl transferase inhibitor (FTI), could be re-purposed to treat progeria
X FTI
Processing of farnesylated prelamin A
Permanently farnesylated prelamin A is the “culprit” that causes disease
FTI Blocks Nuclear Defects of Progeria
S
C O-CH3∆50
aaxC∆50
LaminA
Progerin
Progerin+FTI
S
C O-CH3
From Bench to Bedside Clinical trials with FTI’s show improved
healthspan and lifespan for progeria children
Gordon et al. PNAS (2012), Gordon et al. JAMA (2018)
Our current studies continue a focus on fundamental ZMPSTE24 mechanism
S
C
O-CH3
S
C
O-CH3
ZMPSTE24
• New insights into premature aging
• New insights into normal physiological aging
ZMPSTE24 is a Novel Protease
ZMPSTE24ZMPSTE24 Progeria Mutations
Y399C
L94P
P248L
L462R
L438F L425P
N265S
W340R
Our recent studies suggest potential new treatment strategies
for patients with certain mutations
Disease mutations -> Basic Mechanism -> Personalized Medicine
Atherosclerosis timeline
• Aging is the greatest risk factor for atherosclerosis
• In progeria onset of atherosclerosis is accelerated, in the absence of known risk factors like high cholesterol levels
• Progeria may reveal a specific vulnerability in vessels? Understanding this vulnerability in molecular terms, could lead to more healthy vascular aging for all of us.
Progeria will likely provide insights into the Atherosclerosis of Normal Aging
Atherosclerosis
Michaelis Lab
Eric SpearKhurts Shilgardi
Tim BabatzKaiti Wood
Otto Mossberg
Collaborators
Christine Hrycyna, Purdue
Stephen Young, UCLA
Liz Carpenter, SGC, Oxford, England
Maya Schuldiner, Weizmann, Israel
Dan Berkowitz, Johns Hopkins
Research takes a village!!
A “humanized yeast” system to study prelamin A processing
Catalytic and MAD-B Disease Mutants (blue are unstable)
3myc LMNACT
PTDH3
10His C SIM
ZMPSTE24
Y646 L647
15aa
ZMPSTE24
WB: a-myc
WB: a-HA
% c
leavage
1 2 3 4 5 6 7 8 9 10 11 12
preLA
mLA
0
20
40
60
80
100
ZMPSTE24mutation
Blocking degradation of P248L restores prelamin A cleavage
+ ∆ + ∆ + ∆
WT L94P P248L
DOA10
ZMPSTE24
preLA
mature LA
ZMPSTE24
WB: a-myc
WB: a-HA
Doa10 is a yeast ubiquitin E3 ligase involved in ERAD
Sparing ZMPSTE24 degradation may have therapeutic value for some, but not all
MAD-B patients
