Molecular genetics of early-onset Alzheimer's disease and frontotemporal lobar degeneration

120 Pages·2010·1.42 MB·English

by  Krüger, Johanna

D OULU 2010
D 1074
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UNIVERSITY OF OULU P.O.B. 7500 FI-90014 UNIVERSITY OF OULU FINLAND
ACTA
A UNIVERSITATIS OULUENSIS
A C T A U N I V E R S I T A T I S O U L U E N S I S C
T
A
D
S E R I E S E D I T O R S MEDICA
Johanna Krüger
A
SCIENTIAE RERUM NATURALIUM
MOLECULAR GENETICS OF
J
o
B Professor Mikko Siponen h
a
n EARLY-ONSET ALZHEIMER'S
HUMANIORA n
a

CUniversity Lecturer Elise Kärkkäinen K
DISEASE AND
r
ü
TECHNICA g
e
r FRONTOTEMPORAL LOBAR
D Professor Hannu Heusala
MEDICA DEGENERATION
E Professor Olli Vuolteenaho
SCIENTIAE RERUM SOCIALIUM
F Senior Researcher Eila Estola
SCRIPTA ACADEMICA
G Information officer Tiina Pistokoski
OECONOMICA
University Lecturer Seppo Eriksson
EDITOR IN CHIEF
Professor Olli Vuolteenaho
PUBLICATIONS EDITOR
Publications Editor Kirsti Nurkkala
FACULTY OF MEDICINE,
INSTITUTE OF CLINICAL MEDICINE,
DEPARTMENT OF NEUROLOGY,
ISBN 978-951-42-6314-9 (Paperback)
UNIVERSITY OF OULU;
ISBN 978-951-42-6315-6 (PDF) CLINICAL RESEARCH CENTER,
ISSN 0355-3221 (Print) OULU UNIVERSITY HOSPITAL
ISSN 1796-2234 (Online)

ACTA UNIVERSITATIS OULUENSIS
D Medica 1074
JOHANNA KRÜGER
MOLECULAR GENETICS OF EARLY-
ONSET ALZHEIMER'S DISEASE AND
FRONTOTEMPORAL LOBAR
DEGENERATION
Academic dissertation to be presented with the assent of
the Faculty of Medicine of the University of Oulu for
public defence in Auditorium 8 of Oulu University
Hospital, on 29 October 2010, at 12 noon
UNIVERSITY OF OULU, OULU 2010
Copyright © 2010
Acta Univ. Oul. D 1074, 2010
Supervised by
Docent Anne Remes
Reviewed by
Professor Hannu Kalimo
Docent Minna Pöyhönen
ISBN 978-951-42-6314-9 (Paperback)
ISBN 978-951-42-6315-6 (PDF)
http://herkules.oulu.fi/isbn9789514263156/
ISSN 0355-3221 (Printed)
ISSN 1796-2234 (Online)
http://herkules.oulu.fi/issn03553221/
Cover design
Raimo Ahonen
JUVENES PRINT
TAMPERE 2010
Krüger, Johanna, Molecular genetics of early-onset Alzheimer's disease and
frontotemporal lobar degeneration.
Faculty of Medicine, Institute of Clinical Medicine, Department of Neurology, University of
Oulu, P.O.Box 5000, FI-90014 University of Oulu, Finland; Clinical Research Center, Oulu
University Hospital, P.O. Box 5000, FI-90014 University of Oulu, Finland
Acta Univ. Oul. D 1074, 2010
Oulu, Finland
Abstract
Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are the two most
common neurodegenerative diseases leading to early onset dementia (<65 years). Mutations in
the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes cause
a proportion of familial early-onset AD (eoAD), while the microtubule-associated protein tau
(MAPT) and progranulin (PGRN) mutations have been identified in FTLD patients. Only a few
PSEN1 and APP mutations have previously been found in Finnish AD patients, and one MAPT
mutation in a FTLD family, while the role of PGRN in Finnish FTLD patients is unknown.
Increasing evidence suggests that mitochondrial dysfunction and oxidative stress also play an
important role in neurodegenerative diseases.
The aim here was to investigate the genetics of eoAD and FTLD in the population of the
province of Northern Ostrobothnia, Finland. Sequencing analysis of the APP, PSEN1 and PSEN2
genes was performed to determine whether mutations in these genes could be detected. The MAPT
and PGRN genes were analysed in the FTLD patients by sequencing and MAPT haplotypes were
determined. The contributions of mtDNA and its maintenance enzymes to eoAD and FTLD were
studied by comparing the frequencies of mtDNA haplogroups and their clusters between the
patient groups and controls and by screening for the five common POLG1 mutations (T251I,
A467T, P587L, W748S, Y955C), two common mtDNA mutations (m.3243A>G, m.8344A>G)
and mutations in the PEO1 and ANT1 genes.
This is the first report of a significant association between the mtDNA haplogroup cluster IWX
and FTLD. The H2 MAPT haplotype was also associated with FTLD in our cohort. No significant
differences in the frequencies of the mtDNA haplogroups were observed between the eoAD
patients and controls, nor were there any pathogenic mutations detected in the genes analysed.
The findings suggest that possession of the mtDNA haplogroup cluster IWX and the H2 MAPT
haplotype may be possible risk factors for FTLD in our cohort. The absence of any pathogenic
mutations in the MAPT, PGRN, APP or PSEN genes in our series, together with the previous
reports of only a few mutations found in this region, supports a minor role for these genes in the
aetiology of eoAD and FTLD in Northern Ostrobothnia and indicates that this population may
have its own genetic features. There may be other, still unknown genetic factors to be discovered,
that explain familial diseases in the region.
Keywords: Alzheimer’s disease, amyloid precursor protein, frontotemporal lobar
degeneration, genetics, haplogroup, microtubule associated protein tau, mitochondrial
DNA, polymorphism, presenilin, progranulin

To Ellen and Claes
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Acknowledgements
This study was carried out at the Department of Neurology, University of Oulu,
and the Clinical Research Center, Oulu University Hospital, during the years
2003–2010.
I wish to express my deepest gratitude to my supervisor, Docent Anne Remes,
for introducing me to the fascinating world of science and to this subject. Her vast
knowledge, enthusiasm, endless encouragement and support have been of great
importance for me during these years and essential for the completion of this
thesis. I thank her for her kind and expert guidance throughout this work.
I owe my deepest thanks to Professor Kari Majamaa, head of the Department
of Neurology at the Oulu University Hospital, for his expertise and valuable help
and advice during the preparation of this work. I am grateful to Emeritus
Professor Vilho Myllylä, the former head of the Department of Neurology and
Professor Matti Hillbom for their support and for providing excellent research
facilities for scientific work. I also wish to acknowledge Professor Tatu Juvonen,
head of the Clinical Researh Center, for the research facilities created there.
I wish to express my gratitute to the official referees of this thesis, Professor
Hannu Kalimo and Docent Minna Pöyhönen, for their constructive and valuable
comments and suggestions for improvements. I also wish to thank Malcolm Hicks
for his skilful revision of the English of this thesis and the original papers. Seija
Leskelä is warmly acknowledged for helping to prepare photographs and posters
related to this work.
I am indebted to all the co-authors of the original papers for their valuable
contributions: Anna-Lotta Kaivorinne, Reetta Hinttala, Virpi Moilanen, Katja
Kuivaniemi, Hannu Tuominen and Professor Bjarne Udd. My warmest thanks go
to all the co-researchers and staff of the Research Laboratory of the Department
of Neurology for the stimulating atmosphere that exists there. I have had an
opportunity to work with many wonderful colleagues and friends. I especially
wish to thank Reetta Hinttala, Johanna Annunen-Rasila, Heidi Soini and Anna-
Leena Heula for their precious friendship and support, helpful advice and many
inspiring conversations during these years. I am deeply grateful to Anja
Heikkinen and Pirjo Keränen for their expert technical assistance and friendly
guidance, and for teaching me all the basic methods, when I first started to work
in the laboratory.
I warmly thank all my colleagues at the Department of Neurology for their
support and excellent consultation in clinical work, and indeed the entire staff of
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the department for their co-operation over the years. Special thanks are due to
Mirja Kouvala and Ilona Huovinen for all their help and advice in practical
matters and for friendly secretarial assistance throughout the research.
I express my gratitude to all the patients and their caregivers for participating
in this study.
I thank all my friends for sharing their lives with me and for their support and
relaxing moments spent together which have helped me to continue my work
during these years.
My parents, Kyllikki and Tauno, deserve my warmest thanks for their loving
care and support and continuous encouragenment. I owe my loving thanks to my
brother Antti and my sisters Anna-Maija and Henna, for their support and help
and for sharing many happy moments in life with me. My parents-in-law, Marja-
Liisa and Kurt, are warmly thanked for their love and support and interest in my
work and for taking care of Ellen during critical times. I wish to express my
gratitute to Karina and Mika and their children Verna and Ville for their support
and for wonderful moments spent together.
Above all, my dearest thanks go to my family. There are no words to express
how much I value the endless love and support of my husband Claes. His
understanding attitude, encouragement and confidense in me have been essential
for the completion of this thesis. Our precious daughter Ellen has brought more
joy and happiness in my life than I could ever have imagined. You two are the
most important things in my life.
This work was supported financially by the Finnish Alzheimer Foundation,
the Maire Taponen Foundation, the Orion-Farmos Research Foundation, the
Finnish Alzheimer Foundation for Research, the Finnish Medical Foundation,
Oulu University Hospital and Oulun Yliopiston Tukisäätiö.
Oulu, September 2010 Johanna Krüger
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