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Understanding the Premature Aging Disease Progeria and Its Link to Normal Aging

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Understanding the Premature Aging Disease Progeria and Its Link to Normal Aging 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 1978 1975 Nicholas Nixon Brown Sisters 2006 2001 2011 2014 2017 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 A to Z: Lamin A cleavage by the ZMPSTE24 protease farnesyl S Prelamin A C O-CH3 ZMPSTE24 Mature Lamin A ZMPSTE24 cleavage is critical for health Defective lamin A processing results in the premature aging disease HGPS Sam Berns TEDx talk 2013 “My Philosophy for a Happy Life” >29 million views Sam Sam’s Mom ZMPSTE24 S Mutant Lamin A C Lamin A -O-CH3 HGPS Wild-type 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 S C O-CH ZMPSTE24 3 progeria S C O- CH 3 Early on- there was no connection between lamin A, ZMPSTE24, and progeria HGPS First described by Dr. Jonathan Hutchinson (1886) and Dr. Hastings Gilford (1897) 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 Fatal (death ~age 13) from heart attack or stroke The key advance: HGPS maps to the LMNA gene encoding Lamin A (F. Collins and N. Levy labs, 2003) Brought disparate fields together and galvanized progress Processing of farnesylated prelamin A Permanently farnesylated prelamin A is the “culprit” that causes disease FTI S X Prelamin A * C O-CH3 ZMPSTE24 Mature Lamin A Hypothesis: farnesyl transferase inhibitor (FTI), could be re-purposed to treat progeria FTI Blocks Nuclear Defects of Progeria Lamin A S C O -CH 3 S Progerin ∆50 C O-CH3 Progerin + ∆50 Caax FTI 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 • New insights into premature aging • New insights into normal physiological aging S C O-CH ZMPSTE24 3 S C O- CH 3 ZMPSTE24 is a Novel Protease L438F L425P L462R N265S P248L W340R Y399C L94P ZMPSTE24 Progeria ZMPSTE24 Mutations Disease mutations -> Basic Mechanism -> Personalized Medicine Our recent studies suggest potential new treatment strategies for patients with certain mutations Progeria will likely provide insights into the Atherosclerosis of Normal Aging Atherosclerosis 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. Research takes a village!! Michaelis Lab Eric Spear Khurts Shilgardi Tim Babatz Kaiti Wood Otto Mossberg Collaborators Christine Hrycyna, Purdue Stephen Young, UCLA Liz Carpenter, SGC, Oxford, England Maya Schuldiner, Weizmann, Israel Dan Berkowitz, Johns Hopkins A “humanized yeast” system to study prelamin A processing ZMPSTE24 PTDH3 Y646 L647 10His 3myc LMNACT 15aa C SIM ZMPSTE24 100 mutation 80 60 40 % cleavage 20 preLA 0 WB: a-myc mLA ZMPSTE24 WB: a-HA 1 2 3 4 5 6 7 8 9 10 11 12 Catalytic and MAD-B Disease Mutants (blue are unstable) Blocking degradation of P248L restores prelamin A cleavage Doa10 is a yeast ubiquitin E3 ligase involved in ERAD ZMPSTE24 WT L94P P248L DOA10 + ∆ + ∆ + ∆ preLA mature LA WB: a-myc ZMPSTE24 WB: a-HA Sparing ZMPSTE24 degradation may have therapeutic value for some, but not all MAD-B patients.
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