Presentasjon av Kristin Aaser Lundes doktorgradsarbeid.

1. Parkinsons sykdom på molekylært nivå
Kristin Aaser Lunde
Stavanger universitetsbibliotek 30.10.2014

2. Who am I?
Kristin Aaser Lunde
Born in Oslo, lived in Stavanger since 2003
2012: Master of Science in Biological Chemistry, UiS
2013: Seed grant from Stavanger Helseforskning
2013: Research assistant, NKB
2014: PhD grant from Helse Vest

3. What is my project?
PhD project title:
Early onset dementia in Parkinson’s disease: molecular mechanisms and biomarker discovery
Supervisors: Jodi Maple Grødem and Jan Petter Larsen
A collaboration between Stavanger University, Stavanger University Hospital and St John’s University, New York

4. Today’s presentation
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What is Parkinson’s Disease?
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Why study Parkinson’s disease?
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Ongoing research in Stavanger
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My phd project

5. Parkinson's disease (PD) is a chronic and progressive movement disorder
loss of dopamine-producing neurons in the midbrain (substantia nigra) reduce the brains ability to control movement
Lewy body pathology
Incidence
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More than 1% over the age of 60
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More than 4% over the age of 85
What is Parkinson’s disease ?
Goedert, M. et al. (2012) 100 years of Lewy pathology
Nat. Rev. Neurol. doi:10.1038/nrneurol.2012.242

6. Symptoms of Parkinson’s disease
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Freezing of gait
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Stooped posture, a tendency to lean forward
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Dystonia
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Impaired fine motor dexterity and motor coordination
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Impaired gross motor coordination
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Poverty of movement (decreased arm swing)
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Akathisia
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Speech problems, such as softness of voice or slurred speech caused by lack of muscle control
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Difficulty swallowing
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Sexual dysfunction
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Cramping
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Drooling
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Loss of sense of smell
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Constipation
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REM behavior disorder (a sleep disorder)
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Mood disorders
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Orthostatic hypotension (low blood pressure when standing up).
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Sleep disturbances
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Bladder problems
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Weight loss or gain
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Vision and dental problems
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Fatigue and loss of energy.
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Depression
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Fear and anxiety
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Skin problems
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Cognitive issues, such as memory difficulties, slowed thinking, confusion
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Dementia
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Medication side effects, such as impulsive behaviors
Primary motor symptoms:
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Resting tremor
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Bradykinesia
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Rigidity
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Postural instability
http://neurosciencefundamentals.unsw.wikispaces.net/file/view/parkinsons.PNG/448003022/720x301/parkinsons.PNG

7. Trinh, J. & Farrer, M. (2013) Advances in the genetics of Parkinson disease
Nat. Rev. Neurol. doi:10.1038/nrneurol.2013.132
Parkinson’s disease is a complex disease
Complex disease = diseases that are caused by a number of genetic and environmental factors
Source: Leo Lang /Reuters

8. Disease heterogeneity: Symptoms of PD vary from person to person, as does the rate of progression Personalised medicine: The tailoring of medical treatment to the individual characteristics of each patient or each subgroup of patients. (http://www.ageofpersonalizedmedicine.org/)
http://www.pfizer.ie/personalized_med.cfm
Disease heterogeneity and personalised medicine

9. Population growth
Why is now a good time to study PD?

10. Why is now a good time to study PD?
Brain Research through Advancing Innovative Technologies (BRAIN) Initiative http://www.braininitiative.nih.gov/BRAIN-Brochure.pdf
The Human Genome project 1989 - 2003
-sequence and map all human genes
http://www.genome.gov

11. Stavanger is a good place to study PD
NKB: The Norwegian Centre for Movement Disorders . Highly competent staff of neurologists, nurses, researchers, physiotherapists and psychologists specialising in PD treatment. ParkWest: NKB houses the Norwegian ParkWest study, one of the world’s longest running longitudinal studies of Parkinson’s Disease (PD). As the study approaches its ninth year of follow up, NKB is in a unique position to study the long-term development of PD.

12. The aims of my phd
Lebouvier, Tasselli et al. 2010
Can we find biomolecules that can be utilized to predict PD progression?
Can we detect PD at the presymptomatic stage by the help of biomolecules?
Can we find drug targets to slow or halt disease progression?
Goedert, M. et al. (2012) 100 years of Lewy pathology
Nat. Rev. Neurol. doi:10.1038/nrneurol.2012.242

13. Biomarkers
Biofluids: Cerebrospinal fluid Blood
Techniques: ELISA – for proteins RT-qPCR – for DNA or RNA
a distinct biochemical, genetic, or molecular characteristic or substance that is an indicator of a particular biological condition or process
http://2011.igem.org/wiki/images/thumb/3/31/DTU1_Central_dogma_with_regulators.png/370px- DTU1_Central_dogma_with_regulators.png

14. Enzyme-linked immunosorbent assay (ELISA)
http://medical-dictionary.thefreedictionary.com/ELISA+test

15. Real time quantitative PCR (RT-QPCR)
http://www.thermoscientificbio.com/applications/basic-rt-qpcr/

16. Drug targets
Drug target = the biological target of a pharmacologically active drug compound
Trinh, J. & Farrer, M. (2013) Advances in the genetics of Parkinson disease Nat. Rev. Neurol. doi:10.1038/nrneurol.2013.132

17. Plants
Zebrafish
Worms
Cell cultures
Neurons
Brains
Parkinson’s Disease mechanisms and diagnosis/intervention
Parkinson’s is a highly complex disorder  need for multiple model systems
A complementary approach

18. Localisation assays
Where in the cell can we find our proteins of interest?

19. Interaction studies
Yeast-two-hybrid Bimolecular fluorescence complementation
?

20. C. elegans as a model organism
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Tiny worm 1 mm long
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3 days generation time
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Transparent
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Simple nervous system: 302 neurons
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8 dopaminergic neurons

21. 1.
Parkinson’s disease is a complex disease caused by both genetic and environmental factors
2.
We need to detect and develop biomarkers for:
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Presymptomatic diagnosis
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Prediction of disease progression
3.
We need to develop drugs that can slow down or halt disease progression.
4.
We need to increase our understanding of PD at the molecular level in order to conquer these problems.
Summary

22. Groups:
Funding: NFR, NKB, Norges Parkinsonforbund, Helse Vest, Michal J Fox Foundation
UNIVERSITY OF WESTIMINSTER
Jodi Maple Grødem Maria Doitsidou
NKB
THANK YOU