Neurodegeneration in accelerated aging

190 Pages·2016·41.55 MB·Italian

Neurodegeneration in accelerated aging
Morten Scheibye-Knudsen
Doctoral dissertation
th
October 15 2014
The Faculty of Health and Medical Sciences at the University of Copenhagen has accepted this
dissertation for public defence for the doctoral degree in medicine. Copenhagen, December 11th 2015.

Ulla M. Wewer, Dean, Faculty of Health Sciences, University of Copenhagen

The oral defense will take place on January 14th 2016.

Neurodegeneration in accelerated aging
© Morten Scheibye-Knudsen, 2015
Printed in Denmark 2015
ISBN 978-87-998807-0-6

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Contents
Preface ......................................................................................................................................................... 4
Summary ...................................................................................................................................................... 6
Dansk resumé .............................................................................................................................................. 7
Publications forming the basis of the thesis ................................................................................................ 8
Introduction ................................................................................................................................................. 9
Accelerated aging ...................................................................................................................................... 12
Werner syndrome .............................................................................................................................. 13
Hutchinson-Gilford progeria syndrome ............................................................................................. 13
Nestor-Guillermo progeria syndrome ................................................................................................ 14
Bloom syndrome ................................................................................................................................ 14
Rothmund-Thomson syndrome ......................................................................................................... 15
Dyskeratosis congenita ...................................................................................................................... 15
Fanconi anemia .................................................................................................................................. 16
Ataxia-Telangiectasia ......................................................................................................................... 17
Cockayne syndrome ........................................................................................................................... 17
Xeroderma pigmentosum .................................................................................................................. 18
Mitochondria ............................................................................................................................................. 20
Mitochondrial theory of aging ............................................................................................................... 22
Mitochondrial maintenance ...................................................................................................................... 25
Uncoupling proteins .............................................................................................................................. 25
Antioxidants ........................................................................................................................................... 27
DNA repair ............................................................................................................................................. 28
Mitophagy .............................................................................................................................................. 36
What is a mitochondrial disease? .............................................................................................................. 40
Metabolic and mitochondrial alterations in Cockayne syndrome ............................................................. 42
Defective mitophagy in accelerated aging disorders ................................................................................. 45
Dietary interventions in Cockayne syndrome ............................................................................................ 47
Looking ahead ............................................................................................................................................ 49
Conclusion ................................................................................................................................................. 53
Appendix .................................................................................................................................................... 70

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Preface
The work herein represents my investigation into aspects of mitochondrial maintenance in health and
aging. More specifically, this dissertation attempts to explain the potential involvement of the
mitochondria, in several DNA repair disorders. The work has been conducted over the last 6 years in the
Laboratory of Molecular Gerontology at the National Institute on Aging, NIH, USA in the lab of Dr.
Vilhelm A, Bohr.
First I would like to thank Dr. Vilhelm Bohr. Through the years I have been continuously guided and
challenged by Dr. Vilhelm A. Bohr. He has provided invaluable feedback to all the projects and without
him the science presented herein and this dissertation would certainly never have happened. For this I
offer my deepest gratitude and respect.
I wish to thank Dr. Rafael de Cabo who early on decided to put his faith in me on the off chance that a
particular mouse model might have a metabolic phenotype. This fruitful collaboration has been
instrumental in my continuous development as a scientist.
I must thank all the people in the Laboratory of Molecular Gerontology, NIA, for the fantastic research
environment and friendly atmosphere. In particular, Dr. Evandro Fei Fang should be highlighted for his
immense contribution to the research that forms the basis of this thesis. Dr. Sarah Mitchell, from the
Translational Gerontology Branch, should also be mentioned for tirelessly helping with previous and
ongoing projects.
I wish to acknowledge my collaborators, Drs. Marcus Cooper, Richard Spencer, Hilde Nilsen, James R.
Mitchell, Aswin Mangerich, Mark P. Mattson, Linda H. Bergersen, David G. Le Couteur, Ruin Moaddel,
David Wilson 3rd and Deborah L. Croteau for their important contributions and support of the research.
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I owe thanks to my brother, Dr. Karsten Scheibye-Alsing, who was my greatest inspiration during my
childhood and who has helped me in too many ways to mention. I am deeply grateful for the fantastic
experience it has been to continue our scientific journey together and I look forward to many more
years of shared research.
To my wife, Dr. Pia Steen Petersen, who was close to me despite being separated by the Atlantic Ocean,
who has blessed me with two beautiful daughters, Frida and Anna-My, and who has given me invaluable
scientific feedback on all my manuscripts, thank you.

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Summary
The growing proportion of elderly people represents an increasing economic burden, not least because
of age-associated diseases that pose a significant cost to the health service. Finding possible
interventions to age associated disorders therefore have wide ranging implications. A number of
genetically defined accelerated aging diseases have been characterized that can aid in our
understanding of aging. Interestingly, all these diseases are associated with defects in the maintenance
of our genome. A subset of these disorders, Cockayne syndrome, Xeroderma pigmentosum group A and
ataxia-telangiectasia, show neurological involvement reminiscent of what is seen in primary human
mitochondrial diseases. Mitochondria are the power plants of the cells converting energy stored in
oxygen, sugar, fat, and protein into ATP, the energetic currency of our body. Emerging evidence has
linked this organelle to aging and finding mitochondrial dysfunction in accelerated aging disorders
thereby strengthens the mitochondrial theory of aging. This theory states that an accumulation of
damage to the mitochondria may underlie the process of aging. Indeed, it appears that some
accelerated aging disorders that show neurodegeneration also have mitochondrial dysfunction. The
mitochondrial alterations may be secondary to defects in nuclear DNA repair. Indeed, nuclear DNA
damage may lead to increased energy consumption, alterations in mitochondrial ATP production and
defects in mitochondrial recycling, a term called mitophagy. These changes may be caused by activation
of poly-ADP-ribose-polymerase 1 (PARP1), an enzyme that responds to DNA damage. Upon activation
PARP1 utilizes key metabolites that attenuate pathways that are normally protective for the cell.
Notably, pharmacological inhibition of PARP1 or reconstitution of the metabolites rescues the changes
caused by PARP1 hyperactivation and in many cases reverse the phenotypes associated with accelerated
aging. This implies that modulation of PARP1 or the downstream metabolites may be a therapeutic
strategy for treating accelerated aging disorders and potentially age associated neurological decline
seen in the normal population.
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Dansk resumé
Den stigende andel af ældre i befolkningen udgør en voksende samfundsøkonomisk byrde, ikke mindst
på grund af alders-associerede sygdomme, der udgør en betydelig udgift for sundhedsvæsnet. Det har
derfor stor samfundsmæssig værdi at finde interventioner for aldersbetingede lidelser. En række
genetisk definerede sygdomme udviser accelereret aldring, hvilket giver os enestående muligheder for
at studere og forstå aldringsprocessen. Disse sygdomme er forårsaget af fejl i vedligeholdelse af vores
arvemateriale, DNAet. Af disse udviser patienter der lider af Cockayne syndrom, Xeroderma
pigmentosum gruppe A og ataxia-telangiectasia neurologiske symptomer, der minder om, hvad der
observeres i primære mitokondrielle sygdomme. Mitokondrierne er cellernes kraftværk, der omdanner
oplagret energi i ilt, sukker, fedt og protein til ATP, vores krops energivaluta. En række observationer har
knyttet dette organel til aldring, og muligheden for at finde mitokondriel dysfunktion i lidelser der
udviser accelereret aldring vil derved styrke den mitokondrielle aldringsteori. Det har vist sig, at de
accelererede aldringslidelser der udviser væsentlig neurologisk involvering , også har mitokondriel
dysfunktion. De mitokondrielle ændringer er muligvis en sekundær effekt af dysfunktion i reparationen
af vores arvemateriale i cellekernen. Faktisk ser det ud til, at skade på arvematerialet kan føre til øget
stofskifte, samt ændringer i mitokondriel energiproduktion og i nedbrydning af mitokondrier, en process
kaldet mitophagy. Disse ændringer kan være forårsaget af aktivering af et enzym, poly-ADP-ribose-
polymerase 1 (PARP1), der aktiveres af DNA-skader. Ved aktivering af PARP1 forbruges vigtige
metabolitter, der normalt er beskyttende for cellen. Farmakologisk hæmning af PARP1 eller
genetablering af metabolitterne har vist sig at være gavnlig i forskellige modeller af accelereret aldring.
Dette betyder, at regulering af PARP1, eller metabolitter der forbruges af PARP1, kan være i stand til at
behandle lidelser karakteriseret ved accelereret aldring og potentielt aldersassocieret neurologisk
tilbagegang.
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Publications forming the basis of the thesis
• Scheibye-Knudsen M, Mitchell S, Fang EF, Ward T, Wang J, Dunn CA, Singh N, Veith S, Hasan M,
Mangerich A, Wilson M, Mattson MP, Bergersen LH, Cogger V, Moaddel R, Croteau DL, de Cabo
R, Bohr VA; A High Fat Diet and NAD+ Rescue Premature Aging in Cockayne Syndrome; Cell
Metabolism, In press
• Scheibye-Knudsen M*, Fang EF*, Croteau DL, Bohr VA; Contribution of defective mitophagy to
the neurodegeneration in DNA repair-deficient disorders; Autophagy, 2014 July [*equal
authorship]
• Fang EF*, Scheibye-Knudsen M*, Brace L, Mitchell JR, Nilsen H, Croteau DL, Bohr VA; Defective
Mitophagy in Xeroderma Pigmentosum Group A via Attenuation of the NAD+/SIRT1 Pathway;
Cell, 2014 May [*equal authorship]
• Scheibye-Knudsen M, Scheibye-Alsing K, Canugovi C, Croteau DL, Bohr VA; A novel diagnostic
tool reveals mitochondrial pathology in human diseases and aging; Aging 2013 Mar
• Scheibye-Knudsen M, Croteau DL, Bohr VA; Mitochondrial deficiency in Cockayne syndrome;
Mechanisms of Ageing and Development, 2013 Feb
• Scheibye-Knudsen M, Ramamoorthy M, Sykora P, Maynard S, Lin PC, Minor RK, Wilson III DM,
Cooper M, Spencer R, de Cabo R, Croteau DL, Bohr VA; Cockayne syndrome group B protein
prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy;
The Journal of Experimental Medicine, 2012 Apr
• Scheibye-Knudsen M; Rapamycin – Current and future uses; Chapter 16 in Antitumor Potential
and Other Emerging Medicinal Properties of Natural Compounds by Evandro Fei Fang and Tzi
Bun Ng, Springer 2013 [Book chapter]

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Introduction
The global elderly population has been progressively increasing throughout the 20th century and this
growth is projected to persist into the late 21st century resulting in 20% of the total world population
being aged 65 or more by the year 2100 (Figure 1). 80% of the total cost of health care is accrued after
40 years of age where chronic diseases become prevalent 1, 2. With an exponential increase in health
care costs, it follows that the chronic diseases that accumulate in an aging population poses a serious
socioeconomic problem. Finding treatments to age
15 Aged >85 (%) 25 related diseases, therefore becomes increasingly more
Aged 75-84 (%)
20
Billions) 10 APogpedu l6am5-o7n4 (%) 15 mon (%) pertinent as the population ages. Even more so since
amon ( 5 10 on frac there appears to be a continuous increase in the
opul 5 ulam prevalence of chronic diseases in the aging population 3.
P p
o
P
0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 In other words it seems that the aging population is not
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only growing larger it is also becoming increasingly
Figure 1 Recorded and projected population growth
and age demographics (source: United Nations)
unhealthy compared to the elderly population decades
ago. Research into the mechanisms of aging and age related diseases is therefore imperative.

Recent decades have brought a wealth of knowledge about aging in various organisms. Genetic studies
in yeast and worms have shown several conserved and overlapping molecular pathways that appear to
regulate the aging process 4, 5. These include the insulin and IGF-1 signaling cascades 4, protein synthesis
and quality control 6, regulation of cell proliferation through factors such as mTOR 7, stem cell
maintenance 8 as well as mitochondrial preservation 9. Most of these pathways are conserved through
evolution and appear to regulate aging in many lower organisms. In humans, the discovery of a number
of inherited disorders characterized by accelerated aging and defects in DNA repair has underscored the
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