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Insights into Basic and Clinical Neurobiology Derived from the Analysis of Genetic causes of Neurodegenerative Disease P. St George-Hyslop Centre for Research in Neurodegenerative Diseases, Toronto Western Hospital Research Institute, University of Toronto, Toronto, Ontario, CANADA Overview • Genetics and Biology of Dementias – Alzheimer Disease: • APP, PS1, PS2, APOE ε4 • Other unidentified genes – Fronto-temporal Dementia (& PSP , CBD) • Tau – Dementia with Lewy Bodies • APOE ε4 • Current knowledge of known disease causing pathways; • Application of current knowledge – Prediction of future risks, pharmacogenomics – Design of rational therapeutics Emerging Concept: neurotoxic intra- or extra-cellular deposition of insoluble proteins (-sheet conformation) is the cause of many neurodegenerative diseases Disease Protein Enabling event Alzheimer Disease Frontotemporal Dementia Creutzfeldt-Jacob Familial Encephalopathy Familial British Dementia Parkinson’s Disease Aβ (βAPP) Tau PrPSc (PrPc) Neuroserpin ABri (BRI) α-synuclein β- /γ-secretase ? ? ? Furin cleavage ? What causes Alzheimer Disease? • Genetic Factors (40% of attributable population risk): – Mutations in genes: • • • • • Amyloid Precursor Protein (APP); Presenilin 1 (PS1); Presenilin 2 (PS2); Apolipoprotein E (APOE ε4); Other genes on other chromosomes. • Environmental Factors (± genetic predispositions): – Evidence for specific environmental factors is not robust • • • • Lower childhood education Head Injury Cerebrovascular disease ?Aluminium Genetic and “non-genetic” cases are indistinguishable • Genetic and non-genetic cases have identical: – Clinical features; – Brain pathology; – Brain biochemistry (increased brain levels of Amyloid β-peptide (Aβ) and tau); – Mortality. Genetic Determinants of Alzheimer’s Disease Presenile Familial AD Senile Familial AD Presenilin 1 APP Presenilin 2 gene gene gene (chr 14) (chr 21) (chr 1) age: 25–60 yrs 40–65 yrs 45–84 yrs Sporadic AD APOE 4 allele (chr 19) >50 yrs Other genes yet to be identified The APP gene encodes a Type 1 membrane protien, a fragment of which accumulates in AD brain Citron et al. Nature Med. 3: 67-72, 1997 Aβ peptide domain APP Cell membrane Physiological Endo-proteolytic Processing of APP Citron et al. Nature Med. 3: 67-72, 1997 Pardossi-Piquard R et al. Neuron 46:541-554, 2005. Aβ40 >> Aβ42 -secretase Uptake, chaperoning, & degradation of Aβ by neprilysin, IDE, others g-secretase AICD (?Signalling) a g APP Cell membrane a-secretase Transcriptional induction Mutations Causing Alzheimer Disease cause mis-processing of APP Citron et al. Nature Med. 3: 67-72, 1997 APP mutations Aβ -secretase Uptake, chaperoning, & degradation of Aβ by neprilysin, IDE, others g-secretase AICD (?Signalling) Extracellular a TM domain g Intracellular APP a-secretase FAD-causing mutations in APP are localized in/around the Aβ peptide domain. Codon Mutation 670/671 Lys-Met/ Asn-Leu 692 Ala->Gly 693 Glu->Gln Glu->Gly 694 Asp->Asn 713 Ala->Thr 714 Thr->Ile 715 Val->Met 716 Ile->Val 717 Val->Ile/Phe Phenotype FAD Effect β-secretase cleavage FAD Haemorrhage Haemorrhage Haemorrhage FAD FAD FAD FAD FAD Fibrillogenesis/toxicity Fibrillogenesis/toxicity Fibrillogenesis/toxicity Fibrillogenesis/toxicity N-truncated Aβ42 Extracellular a N-truncated Aβ42 TM domain g Aβ42 Intracellular Aβ42 APP /Gly 723 Leu->Pro FAD Aβ42 FAD-causing mutations in APP are alter the amount or the fibrillogenic potential of Aβ peptide Codon Mutation 670/671 Lys-Met/ Asn-Leu 692 Ala->Gly 693 Glu->Gln Glu->Gly 694 Asp->Asn 713 Ala->Thr 714 Thr->Ile 715 Val->Met 716 Ile->Val 717 Val->Ile/Phe Phenotype FAD Effect β-secretase cleavage FAD Haemorrhage Haemorrhage Haemorrhage FAD FAD FAD FAD FAD Fibrillogenesis/toxicity Fibrillogenesis/toxicity Fibrillogenesis/toxicity Fibrillogenesis/toxicity N-truncated Aβ42 N-truncated Aβ42 Aβ42 Aβ42 /Gly 723 Leu->Pro FAD Aβ42 Mutations Causing Alzheimer Disease cause mis-processing of APP Citron et al. Nature Med. 3: 67-72, 1997 APP mutations PS1/PS2 mutations -secretase A Uptake, chaperoning, & degradation of Aβ by neprilysin, IDE, others g-secretase AICD (?Signalling) Extracellular a TM domain g Intracellular APP a-secretase Naturally Occurring Mutations in Presenilins Alter APP Processing • Predicted to encode homologous polytopic transmembrane proteins (PS1 and PS2). • Contain conserved aspartate residues in transmembrane domains (protease active site). • >100 missense/in-frame splicing mutations in PS1 scattered throughout PS1 molecule; Cytoplasm Membrane Lumen XD XGXGD • > 12 mutations in PS2; • Mutations in PS1 and PS2 often affect orthologous residues. • PS1 and PS2 mutations all alter Aβ production – increase Aβ42. Sherrington et al. Nature 375: 754-760, 1995 Rogaev et al Nature 376: 775-778, 1995 Citron et al. Nature Med. 3: 67-72, 1997 Presenilin Proteins Form a Complex With Nicastrin APH-1 and PEN-2 To Cleave Amyloid Precursor Protein (APP) and generate neurotoxic Aβ peptide. AICD Golgi/ER ε-site Cytoplasm Membrane Lumen/ Cell surface D D Presenilin PEN-2 APH-1 Nicastrin g-site Alzheimer Disease Sherrington, Nature, 1995 Rogaev, Nature, 1995 Katayama, Nature Cell Biol, 1999 Yu, Nature, 2000 Chen, Nature Cell Biol, 2002 Sisodia, Nature Neurosci, 2002 Pardossi-Piquard Neuron, 2005 A _ Similar presenilin-dependent intramembranous cleavages for: •Notch •Delta •p75 •LRP1 •SorLA •Others... Presenilin Mutations Cause Alzheimer Disease by altering γ-secretase cleavage of APP Citron et al. Nature Med. 3: 67-72, 1997 APP mutations PS1/PS2 mutations -secretase A42 g-secretase-42 AICD (?Signalling) Extracellular a TM domain g Intracellular APP a-secretase Uptake, chaperoning, & degradation of Aβ by neprilysin, IDE, others Apolipoprotein E and Alzheimer’s Disease • APOE has 3 variants: 2, 3, 4; • APOE 2 increased frequency in normal elderly, reduced frequency in AD; • APOE 4 associated with Sporadic/familial AD (dose-dependent relationship with age of onset); • APOE 4 association not specific to AD, and not all APOE 4 carriers will succumb to disease. • APOE ε4 appears to block removal of Aβ via LRP receptors, causing accumulation of Aβ. Mutations Causing Alzheimer Disease cause mis-processing of APP Citron et al. Nature Med. 3: 67-72, 1997 APP mutations PS1/PS2 mutations -secretase APOE 4 A g-secretase X ↓ Uptake, chaperoning, & degradation of Aβ AICD (?Signalling) Extracellular a TM domain g Intracellular APP a-secretase A accumulates A aggregates into neurotoxic protofibrils What’s the evidence for this linear pathway? Enhancer and suppressor interactions amongst genes causing Alzheimer Disease Gene interactions in human patients with AD: – APP717 mutation + APOE 4 allele = earlier onset (enhancer); – APP717 mutation + APOE 2 allele = delayed onset (suppressor); – PS1E280A + APOE ε4 = earlier disease (enhancer) – PS2N141V + APOE ε4 = earlier disease (enhancer) . Gene interactions In animal models – APP717 mutation + PS10/0 = no disease (suppressor); – APP717 mutation + PS1mutations = enhanced disease (enhancer). St George-Hyslop et al Science 263:536-537, 1994 Pastor, P. et al. Ann Neurol 54, 163-9 (2003) Suppressor WT/WT ε2/ε3 A717/WT A717/WT ε2/ε3 ε4/ε3 A717/WT ε4/ε3 APP Elderly + APOEold) ε2 carrier V717I(>65yrs eventually asymptomatic developed carrier AD, of APP butV717I at >2 mutation SD beyond mean age-of-onset. A717/WT ε3/ε3 APP genotype (A= APP717) APOE Genotype Enhancer and suppressor interactions amongst genes causing Alzheimer Disease Gene interactions in human patients with AD: – APP717 mutation + APOE 4 allele = earlier onset (enhancer); – APP717 mutation + APOE 2 allele = delayed onset (suppressor); – PS1E280A + APOE ε4 = earlier disease (enhancer) – PS2N141V + APOE ε4 = earlier disease (enhancer) . Gene interactions In animal models – APP717 mutation + PS10/0 = no disease (suppressor); – APP717 mutation + PS1mutations = enhanced disease (enhancer). St George-Hyslop et al Science 263:536-537, 1994 Pastor, P. et al. Ann Neurol 54, 163-9 (2003) Enhancer effect of cross-breeding mutant PS1 and mutant APP mice APP mice – 2 months PS1 mice - 2 months APP x PS1 mice - 2 months Enhancer and suppressor interactions amongst genes causing Alzheimer Disease • Confirms that the known AD genes really do act in the same biochemical pathway affecting APP processing. St George-Hyslop et al Science 263:536-537, 1994 Pastor, P. et al. Ann Neurol 54, 163-9 (2003) What are the other genes? General Paradigms for Gene Discovery LINKAGE BASED •Difficult to collect families •Expensive •Relatively few assumptions •Robust directly observable results CASE : CONTROL ASSOCIATION •Easy to collect sporadic cases •Cheap, quick •Easy to mess up •Requires assumption that cases and controls are from same founder population.. What are the other AD genes? Case:Control > 100 candidate genes reported to be associated with AD; Generally had poor track-record of replication (NB: one or two ‘independent replications’ in the face of many non-replications = non-replication); Family linkage-based method Confirmed localization of an AD-gene to broad region of chromosome 10 containing several hundred genes (the specific gene remains to be found); Confirmed localization of an AD-gene to broad region of chromosome 12 containing several hundred genes (the specific gene remains to be found) What is the role for the microtubule associated protein Tau and neurofibrillary tangles? Fronto-temporal dementia: molecular genetics • Mutations in Tau gene on chromosome 17q in ~10-40% of FTD cases; • Mutations disturb binding of tau protein to microtubules, causing accumulation of free unbound tau; • Free unbound tau aggregates into fibrils and these then coalesce into paired helical filaments as the neurofibrillary tangle; • The tau fibrils then injure cells (but mechanism is unclear). Conclusions to Be Drawn From the Discovery of Pathogenic Mutations in Tau in FTD • Disturbed tau/microtubule homeostasis, regardless of cause, is toxic to neurons A accumulation initiates a biochemical cascade leading to neuronal death Dementia Cause: (eg gene defect) A peptide accumulation Neuronal injury Altered Tau metabolism Neuronal dysfunction and death How is this knowledge applied for patients? • Adjunctive Diagnostics • Therapeutic Targets Prediction of future risk for AD? • Testing and genetic counselling feasible for: – – – Highly penetrant forms, with Clear patterns of inheritance, and Relatively predictable age-of-onset: • • • • PS1 APP Tau Testing and genetic counselling not presently feasible/useful for: – Incompletely penetrant forms with variable age-of-onset: • • • – PS2 APOE Putative genes on chromosomes 10, 12 etc NB: Advent of future therapies may make even fuzzy-risk data from such genes useful Can Genetics Predict Conversion From MCI To AD? • Intuitive expectation: – Carrier of AD risk allele with MCI would be more likely to convert to AD. • Actual data available only for ApoE • ApoE ε4 predictive: – Petersen et al, JAMA 274: 538,1995 – Bartrez-Faz et al, JAGS 49: 485, 2001 • ApoE ε4 not predictive: – Marquis et al, Arch. Neurol. 59: 601, 2002 – Tierney et al, Neurol. 46: 149, 1996. Prediction of therapeutic response • Theoretically reasonable; • Remains to be validated. Gene 1 Step 1 Gene 2 Step 2 Rx 1 Environment factor 1 Step 3 Step 4 Rx 2 AD Using A accumulation pathways as a target for therapies Dementia Cause: (eg gene defect) A peptide accumulation Neuronal injury Altered Tau metabolism Neuronal dysfunction and death Exploiting Knowledge Gained to Create New Diagnostics and Therapeutics •Anti-A antibodies to remove A; •Block enzymes; •Block aggregation. Cause: (eg gene defect) X A peptide accumulation Dementia Neuronal injury Neuronal dysfunction and death Altered Tau metabolism Janus et al Nature. 408: 979-982, 2000, McLaurin et al, Nature submitted, 2004 How can the amyloid cascade be blocked? Citron et al. Nature Med. 3: 67-72, 1997 Pharma: Pharma: A -secretase Vaccine: toxic g-secretase Uptake, chaperone, or degradation (by neprilysin). AICD (?Signalling) a Pharma g X APP Cell membrane A accumulates A aggregates into neurotoxic protofibrils Conclusions: • All known genes causing AD modulate APP and Aβ processing; • Neurodegeneration from mutations in tau prove that tau accumulation is also a toxic event (regardless of whether caused by mutation in tau or due to Aβ accumulation) • Knowledge of pathway will provide targets for disease-modifying therapies. Acknowledgements S. Arawaka F. Chen L. Farrer, P. Fraser YJ. Gu H. Hasegawa M. Ikeda T. Katayama T. Kawarai G. Levesque M. Nishimura A. Petit E. Rogaeva N. Sanjo P. St George-Hyslop D. Westaway Canadian Institutes of Health Research Howard Hughes Medical Institute Alzheimer Society of Ontario, Canadian Genetic Diseases Network A. Bruni, F. Checler JF Foncin, G. Marcon, M. Mortilla, A. Orlacchio, E. Paitel S. Piacentini, L. Pinessi, I. Rainero, S. Sorbi, R. Tupler, G. Vaula CONTACT INFORMATION • Analysis of familial cases: P. St George-Hyslop, University of Toronto tel: 416-978-7460 [email protected] • Animal models (transgenic mice etc): David Westaway [email protected] • Reagents (clones, cell lines, antibodies, etc) P. St George-Hyslop, University of Toronto [email protected]