Investigating the Endo-Lysosomal System in Major Neurocognitive Disorders Due to Alzheimer’s Disease, Frontotemporal Lobar Degeneration and Lewy Body Disease: Evidence for SORL1 as a Cross-Disease Gene

Dysfunctions in the endo-lysosomal system have been hypothesized to underlie neurodegeneration in major neurocognitive disorders due to Alzheimer’s disease (AD), Frontotemporal Lobar Degeneration (FTLD), and Lewy body disease (DLB). The aim of this study is to investigate whether these diseases share genetic variability in the endo-lysosomal pathway. In AD, DLB, and FTLD patients and in controls (948 subjects), we performed a targeted sequencing of the top 50 genes belonging to the endo-lysosomal pathway. Genetic analyses revealed (i) four previously reported disease-associated variants in the SORL1 (p.N1246K, p.N371T, p.D2065V) and DNAJC6 genes (p.M133L) in AD, FTLD, and DLB, extending the previous knowledge attesting SORL1 and DNAJC6 as AD- and PD-related genes, respectively; (ii) three predicted null variants in AD patients in the SORL1 (p.R985X in early onset familial AD, p.R1207X) and PPT1 (p.R48X in early onset familial AD) genes, where loss of function is a known disease mechanism. A single variant and gene burden analysis revealed some nominally significant results of potential interest for SORL1 and DNAJC6 genes. Our data highlight that genes controlling key endo-lysosomal processes (i.e., protein sorting/transport, clathrin-coated vesicle uncoating, lysosomal enzymatic activity regulation) might be involved in AD, FTLD and DLB pathogenesis, thus suggesting an etiological link behind these diseases.

[1]  J. Hardy,et al.  SORL1 mutation in a Greek family with Parkinson's disease and dementia , 2021, Annals of clinical and translational neurology.

[2]  Jiou Wang,et al.  NDST3 deacetylates α‐tubulin and suppresses V‐ATPase assembly and lysosomal acidification , 2021, The EMBO journal.

[3]  Sonja W. Scholz,et al.  Identification of sixteen novel candidate genes for late onset Parkinson’s disease , 2021, Molecular Neurodegeneration.

[4]  P. Scheltens,et al.  SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network , 2021, Cell reports.

[5]  G. Binetti,et al.  Plasma Extracellular Vesicle Size and Concentration Are Altered in Alzheimer’s Disease, Dementia With Lewy Bodies, and Frontotemporal Dementia , 2021, Frontiers in Cell and Developmental Biology.

[6]  L. Ouyang,et al.  Targeting Lysosomal Degradation Pathways: New Strategies and Techniques for Drug Discovery. , 2021, Journal of medicinal chemistry.

[7]  B. Asselbergh,et al.  Contribution of rare homozygous and compound heterozygous VPS13C missense mutations to dementia with Lewy bodies and Parkinson’s disease , 2021, Acta Neuropathologica Communications.

[8]  C. Crews,et al.  Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs , 2021, The Journal of biological chemistry.

[9]  Silvio C. E. Tosatto,et al.  The InterPro protein families and domains database: 20 years on , 2020, Nucleic Acids Res..

[10]  N. Seyfried,et al.  Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations , 2020, Acta neuropathologica communications.

[11]  J. Quinn,et al.  Genetic Risk Profiling in Parkinson’s Disease and Utilizing Genetics to Gain Insight into Disease-Related Biological Pathways , 2020, International journal of molecular sciences.

[12]  K. Jellinger.  Neuropathological assessment of the Alzheimer spectrum , 2020, Journal of Neural Transmission.

[13]  M. Cookson,et al.  The Parkinson’s Disease Protein LRRK2 Interacts with the GARP Complex to Promote Retrograde Transport to the trans-Golgi Network , 2020, Cell reports.

[14]  J. Toldi,et al.  Exploring the Etiological Links behind Neurodegenerative Diseases: Inflammatory Cytokines and Bioactive Kynurenines , 2020, International journal of molecular sciences.

[15]  R. Hunt,et al.  Patho-mechanism Heterogeneity in the Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Disease Spectrum: Providing Focus through the Lens of Autophagy. , 2020, Journal of molecular biology.

[16]  P. Mathews,et al.  Exosome Production Is Key to Neuronal Endosomal Pathway Integrity in Neurodegenerative Diseases , 2019, Front. Neurosci..

[17]  Y. Goshima,et al.  Network-guided analysis of hippocampal proteome identifies novel proteins that colocalize with Aβ in a mice model of early-stage Alzheimer’s disease , 2019, Neurobiology of Disease.

[18]  G. Binetti,et al.  The Missing Heritability of Sporadic Frontotemporal Dementia: New Insights from Rare Variants in Neurodegenerative Candidate Genes , 2019, International journal of molecular sciences.

[19]  S. Pulit,et al.  The project MinE databrowser: bringing large-scale whole-genome sequencing in ALS to researchers and the public , 2019, Amyotrophic lateral sclerosis & frontotemporal degeneration.

[20]  D. Campion,et al.  SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data , 2019, Acta Neuropathologica.

[21]  K. Sleegers,et al.  Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability , 2019, Acta Neuropathologica.

[22]  I. Mackenzie,et al.  Review: Neuropathology of non‐tau frontotemporal lobar degeneration , 2019, Neuropathology and applied neurobiology.

[23]  Y. Okuno,et al.  Fibronectin type III domain-containing protein 5 interacts with APP and decreases amyloid β production in Alzheimer’s disease , 2018, Molecular Brain.

[24]  V. Mäkinen,et al.  Genetic variation within endolysosomal system is associated with late-onset Alzheimer’s disease , 2018, Brain : a journal of neurology.

[25]  T. Uchihara,et al.  Reader response: Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB consortium , 2018, Neurology.

[26]  Chao Wang,et al.  Endo-lysosomal dysfunction: a converging mechanism in neurodegenerative diseases , 2018, Current Opinion in Neurobiology.

[27]  M. Cheetham,et al.  DNAJ Proteins in neurodegeneration: essential and protective factors , 2018, Philosophical Transactions of the Royal Society B: Biological Sciences.

[28]  G. Binetti,et al.  The Heritability of Frontotemporal Lobar Degeneration: Validation of Pedigree Classification Criteria in a Northern Italy Cohort. , 2017, Journal of Alzheimer's disease : JAD.

[29]  Annelot M. Dekker,et al.  Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis , 2017, European Journal of Human Genetics.

[30]  Wei‐Ju Lee,et al.  SORL1 gene, plasma biomarkers, and the risk of Alzheimer’s disease for the Han Chinese population in Taiwan , 2016, Alzheimer's Research & Therapy.

[31]  Mikyoung Park,et al.  Palmitoylation in Alzheimer's disease and other neurodegenerative diseases. , 2016, Pharmacological research.

[32]  Joan Teyra,et al.  ELASPIC web-server: proteome-wide structure-based prediction of mutation effects on protein stability and binding affinity , 2016, Bioinform..

[33]  Michelle K. Cahill,et al.  Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation , 2016, Cell.

[34]  G. Forloni,et al.  Loss of exosomes in progranulin-associated frontotemporal dementia , 2016, Neurobiology of Aging.

[35]  Giuliano Binetti,et al.  A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease , 2016, Acta Neuropathologica.

[36]  D. Underhill,et al.  C9orf72 is required for proper macrophage and microglial function in mice , 2016, Science.

[37]  W. Mandemakers,et al.  DNAJC6 Mutations Associated With Early‐Onset Parkinson's Disease , 2016, Annals of neurology.

[38]  Ru-jing Ren,et al.  The endosomal-lysosomal system: from acidification and cargo sorting to neurodegeneration , 2015, Translational Neurodegeneration.

[39]  Michel Goedert,et al.  Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein , 2015, Science.

[40]  H. Rehm,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[41]  Yufeng Shen,et al.  Coding mutations in SORL1 and Alzheimer disease , 2015, Annals of neurology.

[42]  X. Breakefield,et al.  Emerging Roles of Extracellular Vesicles in the Nervous System , 2014, The Journal of Neuroscience.

[43]  Alexander Gerhard,et al.  Frontotemporal dementia and its subtypes: a genome-wide association study , 2014, The Lancet Neurology.

[44]  D. Holtzman,et al.  Lysosomal Sorting of Amyloid-β by the SORLA Receptor Is Impaired by a Familial Alzheimer’s Disease Mutation , 2014, Science Translational Medicine.

[45]  A. Tolun,et al.  DNAJC6 is responsible for juvenile parkinsonism with phenotypic variability. , 2013, Parkinsonism & related disorders.

[46]  M. Rieder,et al.  Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. , 2012, American journal of human genetics.

[47]  Katherine R. Smith,et al.  Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. , 2012, American journal of human genetics.

[48]  K. Kaestner,et al.  A Deleterious Mutation in DNAJC6 Encoding the Neuronal-Specific Clathrin-Uncoating Co-Chaperone Auxilin, Is Associated with Juvenile Parkinsonism , 2012, PloS one.

[49]  B Croisile,et al.  High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease , 2012, Molecular Psychiatry.

[50]  N. Hübner,et al.  Identification of Alzheimer disease risk genotype that predicts efficiency of SORL1 expression in the brain. , 2012, Archives of neurology.

[51]  P. D. Rijk,et al.  Optimized filtering reduces the error rate in detecting genomic variants by short-read sequencing , 2011, Nature Biotechnology.

[52]  Nick C Fox,et al.  Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. , 2011, Brain : a journal of neurology.

[53]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease: Report of the NINCDS—ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease , 2011, Neurology.

[54]  Chris Gardiner,et al.  Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission , 2011, Neurobiology of Disease.

[55]  J. Morris,et al.  The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[56]  B. Miller,et al.  Classification of primary progressive aphasia and its variants , 2011, Neurology.

[57]  M. DePristo,et al.  The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. , 2010, Genome research.

[58]  D. Westaway,et al.  Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 Mutations , 2010, Cell.

[59]  P. De Camilli,et al.  Endocytosis and clathrin-uncoating defects at synapses of auxilin knockout mice , 2010, Proceedings of the National Academy of Sciences.

[60]  G. Binetti,et al.  Progranulin Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide , 2009, Neurobiology of Disease.

[61]  A. Ariza,et al.  Molecular Pathology of Lewy Body Diseases , 2009, International journal of molecular sciences.

[62]  K. Jellinger.  Neuropathological Aspects of Alzheimer Disease, Parkinson Disease and Frontotemporal Dementia , 2008, Neurodegenerative Diseases.

[63]  Claudio Soto,et al.  Protein misfolding and neurodegeneration. , 2008, Archives of neurology.

[64]  E. Eisenberg,et al.  Multiple Roles of Auxilin and Hsc70 in Clathrin‐Mediated Endocytosis , 2007, Traffic.

[65]  K. Lunetta,et al.  The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease , 2007, Nature Genetics.

[66]  Vanessa Schmidt,et al.  Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11. , 2006, Biochemistry.

[67]  Arlo Z. Randall,et al.  Prediction of protein stability changes for single‐site mutations using support vector machines , 2005, Proteins.

[68]  J. Neuhaus,et al.  Comparison of family histories in FTLD subtypes and related tauopathies , 2005, Neurology.

[69]  Piero Fariselli,et al.  I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure , 2005, Nucleic Acids Res..

[70]  E. Chouery,et al.  Adult neuronal ceroid lipofuscinosis with palmitoyl‐protein thioesterase deficiency: First adult‐onset patients of a childhood disease , 2001, Annals of neurology.

[71]  K. Wisniewski,et al.  Genotype-phenotype correlations in neuronal ceroid lipofuscinosis due to palmitoyl-protein thioesterase deficiency. , 1999, Molecular genetics and metabolism.

[72]  J. Brion,et al.  Neurofibrillary Tangles and Alzheimer’s Disease , 1998, European Neurology.

[73]  K. Wisniewski,et al.  Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S. , 1998, The Journal of clinical investigation.

[74]  J. Growdon,et al.  Segregation analysis reveals evidence of a major gene for Alzheimer disease. , 1991, American journal of human genetics.

[75]  D. Campion,et al.  Biallelic Loss of Function of SORL1 in an Early Onset Alzheimer's Disease Patient. , 2018, Journal of Alzheimer's disease : JAD.

[76]  Seunggeun Lee,et al.  An efficient resampling method for calibrating single and gene-based rare variant association analysis in case-control studies. , 2016, Biostatistics.

[77]  P. Bol.  [Anxiety disorders]. , 2001, Nederlands tijdschrift voor tandheelkunde.