Genes involved in early aging and cognitive loss: Dr. Andrea Pilotto is PKU also at risk? Prof. Daniela Berg Prof. Walter Maetzler Department of Neurodegenerative Disorders Hertie Institut for Clinical Brain Research DZNE German Center For Neurodegenerative Disorders Uniklinikum Tübingen Uniklinikum Tübingen Genes involved in early aging and cognitive loss: is PKU also at risk? Neurodegenerative disorders: genes and proteins Link between PKU and neurodegenerative disorders Role of treatment, diet and normal aging How can we detect neurodegenerative disorders in PKU? Uniklinikum Tübingen PKU Neurodegenerative disorders Genes? Protein aggregation? proteosome lysosome PKU and Neurodegenerative disorders Really at-risk population? Which neurodegenerative disorder? A model for neurodegeneration? Diet and PKU treatment? ADULT- ETPKU subjects: High heterogeneity: Different mutations Psycho-Social level and cognition Diet and treatment duration Trefz 2011 Mol Genet Metabol Progressive neuropsychiatric manifestations of PKU in adulthood Parkinsonism Psychiatric involvement Spastic paraparesis Many cases had no diet Thomspon 1990 Lancet Daelman 2014 Rev Neurol What is the role of White-Matter (WM) damage? Are all WM lesions reversible? Phenylalanine long-term toxicity? Neurodegenerative disorders Aβamyloid Alzheimer’s Disease: Aβ-amyloid and TAU pathology TAU Jucker Nature 2013 Lewy Body Parkinson’s Disease: Lewy Body and alpha-synuclein Alzheimer’s Disease 5.2 million cases in U.S.A Incidence and prevalence increased with age Parkinson’s 1,5 million cases in U.S.A. Disease Peak incidence by the age of 60-65 years Early-Onset Disease Late-Onset “classical” Disease 2-5% Early-Onset Alzheimer’s Disease 10-15% Early-Onset Parkinson’s Disease Number of cases age Probability of monogenic cause of Disease GENETICS Genetics of Alzheimer’s Disease APP, PSEN1, PSEN2 APOE Manolio 2009 Nature Genome-wide association studies ABCA7, APOE, BIN1, CASS4, CD2AP, CELF1, CLU, CR1, EPHA1, FERMT2, FRMD4A, HLADRB1, INPP5D, MEF2C, MS4A6A, NME8, PICALM, PTK2B, SCL24A4, SORL1 Alzheimer’s Disease PSEN1, PSEN2 APP APOE genetics APOE “Amyloid Cascade Hypothesis” Cummings 2004 NEJM Amyloid pathology and PKU Reches 2002 J Biol Chem Short aromatic peptide fragments are fybrillogenic Diphenylalanine represent the core-peptide of Aβ-amyloid Abramovic Nature Ch Biol 2012 Phenylalanine assembly into toxic fibrils suggests amyloid etiology in phenylketonuria In vitro assembly Phenylalanine fibrils and Cellular toxicity Phenylalanine long-term toxicity? In vivo staining Parkinson’s Disease Genetics Monogenic forms Autosomal Dominant Autosomal Recessive SNCA (PARK1/4) LRRK2 (PARK8) VPS35 EIF4G1 GBA PARKIN (PARK2) PINK1 (PARK6) DJ1 (PARK7) GBA ATP13A2 (PARK9) PLA2G6 (PARK14) FBXO7 (PARK15) Sporadic forms LRRK2 GBA SNCA MAPT HLA SMPD1 Parkinson’s Disease Genetics and pathophysiology Obeso Nature 2010 Gaucher and Parkinsons’s Lysosomal involvement Rosenbloom 2011 Blood Cell Mol Dis disease 8–12% of Gaucher patients have Parkinson’s disease McNeill 2012 JNNP Parkinson risk in heterozygous GBA mutations carriers is 10–15% by age 80 Lysosomes and Parkinsons’s disease Sidransky 2012 Lancet Neurol Parkinson’s Disease and PKU: a possible link? Porta 2011 Mol Genet Metab Higher lysosomal activity compared with age-matched controls Phenylalanine long-term toxicity and lysosomes? Dopamine and serotonin Feillet 2011 Pediatrics deficits Parkinsonism and psychiatric involvement in PKU Late-onset PKU case with parkinsonism Daelman 2014 Rev Neurol Abnormal pre-synaptic dopamine activity Alzheimer’s Disease BIOMARKERS Parkinson’s Disease From monogenic and sporadic Bateman 2012 cases.. NEJM Jack 2013 Neuron Berg 2012 Mov Disord Hyposmia, autonomic dysfunction REM behavioral disorders, Depression Enlarged Hyperechogenic Substantia Nigra Combination of CSF and imaging markers Berg 2001 Neurology Alzheimer’s Disease Parkinson’s Disease BIOMARKERS In Early-treated Phenylketonuria Adults patients ? EN-ETPKU Study a pilot-study to assess the risk of Early Neurodegeneration in early-treated PKU adult patients Prof. Trefz Prof. Freisinger Klinik für Kinder und Jugendmedizin Reutlingen Prof. Hoffmann Zentrum für Kinder und Jugendmedizin Heidelberg University Phenylalanine long-term brain toxicity: proposed mechanisms Amyloid Deposition Increased lysosomal activity Alzheimer’s Disease Parkinson’s Disease WM-related damage? Modified by Feillet F , Pediatrics (2010) Thank you.. Prof. Daniela Berg Prof. Walter Maetzler Department of Neurodegenerative Disorders Hertie Institut for Clinical Brain Research DZNE German Center For Neurodegenerative Disorders Uniklinikum Tübingen Prof. Trefz Prof. Freisinger Klinik für Kinder und Jugendmedizin Reutlingen Uniklinikum Tübingen
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