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What a Change! WHAT A CHANGE! A research on the implications and phylogeny of single nucleotide polymorphisms (SNPs) in Alzheimer’s and Parkinson’s diseases Joana Bordas Solé Carla F. Cadenet Cecília Vila Riera December 2015 2nd Batx Escola Sant Gregori Tutor: Begoña Vendrell Simón 2 3 To those who suffer, have suffered or will suffer from a neurodegenerative disease. All the effort and time we have devoted on this project is for them, so one day they will have a better life. 4 “The total amount of suffering per year in the natural world is beyond all decent contemplation. During the minute that it takes me to compose this sentence, thousands of animals are being eaten alive, many others are running for their lives, whimpering with fear, others are slowly being devoured from within by rasping parasites, thousands of all kinds are dying of starvation, thirst, and disease. It must be so. If there ever is a time of plenty, this very fact will automatically lead to an increase in the population until the natural state of starvation and misery is restored. In a universe of electrons and selfish genes, blind physical forces and genetic replication, some people are going to get hurt, other people are going to get lucky, and you won't find any rhyme or reason in it, nor any justice. The universe that we observe has precisely the properties we should expect if there is, at bottom, no design, no purpose, no evil, no good, nothing but pitiless indifference.” Richard Dawkins, River Out of Eden: A Darwinian View of Life 5 Acknowledgements The success and final outcome of this project required a lot of guidance and assistance from many people. In the following paragraphs we would like to take a minute to thank them. To begin with, this project could not have been done without the previous work of all the scientists that have shared their discoveries, so we would like to thank them all. We would like to especially thank Dr. Gerard Muntané and Dr. Gabriel Santpere who took the time to explain the basics of genetics to us and guide us throughout all the project. Apart from that, Dr. Santpere posed this research challenge to us, which was the starting point of our project. We would also like to thank Dr. Josep Prous, who kindly made some time to share his research with us. Moreover, we are also grateful to our English teacher, Miss Usoa Sol, who made an enormous effort to correct this project in spite of not being her field of expertise. Last but not least, we would like to especially thank our amazing tutor, Begoña Vendrell, for giving us the opportunity to do such an uncommon project. She not only helped us with all the questions about the project but she also encouraged us during all the process. Her energy and enthusiasm in this project inspired us to keep on working at our best. It is undeniable that we could not have done it without her. 6 Abbreviations A: Adenine. AA or aa: Amino acid. AD: Alzheimer’s Disease. Ala (A): Alanine. APOE: Apolipoprotein E. AP: Proteic part. APP: Amyloid precursor protein. Arg (R): Arginine. Asn (N): Asparagine. Asp (D): Aspartate. ATP13A2: Probable cation-transporting ATPase 13A2 (PARK9). C: Cytosine. CDS: Coding sequence.cDNA: coding Deoxyribonucleic acid. CNS: Central Nervous System. Cys (C): Cysteine. DJ1: Protein deglycase DJ-1. (ENS)EMBL: European Molecular Biology Laboratory. EOAD: Early-onset Alzheimer's Disease. EOPD: Early-onset Parkinson's Disease. FAD: Familial Alzheimer’s Disease. FBXO7:F-box only protein 7. G: Guanine. Gln (Q): Glutamine. Glu (E): Glutamate. Gly (G): Glycine. His (H): Histidine. Ile (I): Isoleucine. LB: Lewy Bodies. Leu (L): Leucine. LN: Lewy Neurites. LRRK2: Leucine-rich repeat serine/threonine-protein kinase 2. Lys (K): Lysine. Met (M): Methionine. mRNA: messenger ribonucleic acid. ND: Neurodegenerative Disease. OMIM: Online Mendelian Inheritance in Man. 7 PARK2: Parkin (ligase). PD: Parkinson’s Disease. Phe (F): Phenylalanine. PINK1: PTEN-induced putative kinase 1. PLA2G6: 85/88 kDa calcium-independent phospholipase A2. Pro (P): Proline. PSEN 1: Presenilin 1. PSEN 2: Presenilin 2. RNA: Ribonucleic acid. Ser (S): Serine. SNCA: Alpha synuclein SNP: Single Nucleotide Polymorphism T: Thymine. Thr (T): Threonine. Trp (W): Tryptophan. Tyr (Y): Tyrosine. U: Uracil. UCSC: University of California, Santa Cruz (Genome Browser). VPS35: Vacuolar protein sorting-associated protein 35. Val (V): Valine. 8 CONTENTS 0- Introduction and main objectives of this piece of work 13 1- Introduction to molecular aspects of neurodegenerative diseases 16 1.1 Neurodegenerative diseases 16 1.1.1 Tauopathies 16 1.1.1.1 Alzheimer’s Disease (AD) 18 1.1.2 α-synucleinopathies 20 1.1.2.1 Parkinson’s Disease (PD) 20 1.1.3 Comparison between AD (tauopathy) and PD (synucleinopathy) 22 1.2 Implication of gene mutations in diseases 23 1.2.1 Penetrance 24 1.2.2 SNP Mutations and evolution: the dN/dS ratio 24 1.3 Protein expression and its implication in diseases 26 1.3.1 Deoxyribonucleic acid 26 1.3.2 Transcription of DNA and formation of the mRNA 27 strand 1.3.3 mRNA translation 28 1.3.4 Amino acids 28 1.3.5 Proteins involved in EOAD and EOPD 31 2- Working questions and hypothesis 34 3- Methodology 36 4- Results and discussion 61 4.1 Mutations leading to EOAD and comparison with animals’ 62 genes 4.1.1 APP gene 62 4.1.2 PSEN1 gene 66 4.1.3 PSEN2 gene 74 4.2 Mutations leading to EOPD and comparison with animals’ 75 genes 4.2.1 DJ1 gene 75 4.2.2 PLA2G6 gene 77 4.2.3 PINK1 gene 80 4.2.4 VPS35 gene 83 9 4.2.5 SNCA gene 84 4.2.6 ATP13A2 gene 86 4.2.7 FBXO7 gene 88 4.2.8 LRRK2 gene 90 4.2.9 PARK2 gene 93 4.3 Quantification of synonymous and non-synonymous changes 95 4.4 dN/dS ratio 97 4.5 Number of mutations and phylogenetic distance 99 5- Conclusions 102 6- Future research 104 7- Glossary 105 8- References: bibliography and webgraphy 109 9- Annexes 111 9.1 Geographic origin of the studied AD mutations 111 9.2 Geographic origin of the studied PD mutations 112 9.3 CD-rom of supplementary materials 113 10 Abstract This project studies the two most important neurodegenerative diseases: Alzheimer's and Parkinson's. It focuses on the genetic aspect of these diseases, studying the genes that codify for the proteins affected in these pathologies. These are APP, PSEN1 and PSEN2 for AD, and LRRK2, PLA2G6, DJ1, PINK1, ATP13A2, PARK2, FBXO7, SNCA and VPS35 for PD. Our objectives were to analize the SNP mutations that lead to the malformation of the proteins with 100% penetrance leading to EOAD and EOPD and then compare the codons affected with some animals' genome. As for the study of the mutations, we found that they are negative selected and that the change of amino acid does not have to be an extreme change, because sometimes even if the change is minimum it can lead to the malformation of the protein. This is because what matters most about a protein is its function and therefore the tertiary structure. When doing the alignments with the animals' genome, we found that there are some animals that present the mutation that in humans lead to EOAD or EOPD but they do not have the disease. Why they do not have the disease is one of the questions we could not answer but we formulated some hypotheses. We also found that the animals futher away from humans in the phylogenetic tree present more differences in the codons involved. Este proyecto aborda las dos enfermedades neurodegenerativas más importantes: Alzheimer y Parkinson. Se centra en la parte genética de estas enfermedades, estudiando los genes que codifican por las proteinas afectadas en estas patologías. Estos son APP, PSEN1 y PSEN2 para el Alzheimer, y LRRK2, PLA2G6, DJ1, PINK1, ATP13A2, PARK2, FBXO7, SNCA y VPS35 para el Parkinson. Nuestros objetivos eran analizar las mutaciones que derivan en la malformación de las proteinas afectadas con 100% de penetrancia en el Alzheimer y el Parkinson, y luego comparar los codones afectados con el genoma de algunos animals elegidos. Respecto el estudio de las mutaciones, encontramos que están seleccionadas negativamente y que el cambio de aminoácido no tiene porque ser un cambio 11 extremo, a veces incluso un cambio mínimo puede causar la malformación de la proteína. Esto es así ya que lo realmente importante es la función de la proteína, es decir, la estructura terciaria de esta. Cuando llevamos a cabo los alineamientos con los genomas de los animales, encontramos que algunos animales tienen las mutaciones que en humanos causan EOAD o EOPD pero no presentan las enfermedades. Por qué no tienen las enfermedades es una pregunta que no pudimos responder pero formulamos algunas hipótesis. Hemos podido comprobar también que los animales que se encuentran más lejos en el árbol filogenético presentan más diferencias en los codones involucrados. Aquest treball de recerca aborda les dues malalties neurodegeneratives més importants: l'Alzheimer i el Parkinson. L'estudi es centra en la part genètica d'aquetes malalties, estudiant els gens que codifiquen per les proteïnes afectades en aquetes patologies. Aquets són APP, PSEN1 i PSEN2 en l'Alzheimer, i LRRK2, PLA2G6, DJ1, PINK1, ATP13A2, PARK2, FBXO7, SNCA i VPS35 en el Parkinson. Els nostres objectius eren analitzar les mutacions que deriven en la malformació de les proteïnes afectades en l'Alzheimer i el Parkinson, i després comparar els codons afectats amb el genoma d'alguns animals escollits.
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