Quantitative Interaction Proteomics of Neurodegenerative Disease Proteins

Several proteins have been linked to neurodegenerative disorders (NDDs), but their molecular function is not completely understood. Here, we used quantitative interaction proteomics to identify binding partners of Amyloid beta precursor protein (APP) and Presenilin-1 (PSEN1) for Alzheimer's disease (AD), Huntingtin (HTT) for Huntington's disease, Parkin (PARK2) for Parkinson's disease, and Ataxin-1 (ATXN1) for spinocerebellar ataxia type 1. Our network reveals common signatures of protein degradation and misfolding and recapitulates known biology. Toxicity modifier screens and comparison to genome-wide association studies show that interaction partners are significantly linked to disease phenotypes in vivo. Direct comparison of wild-type proteins and disease-associated variants identified binders involved in pathogenesis, highlighting the value of differential interactome mapping. Finally, we show that the mitochondrial protein LRPPRC interacts preferentially with an early-onset AD variant of APP. This interaction appears to induce mitochondrial dysfunction, which is an early phenotype of AD.

[1]  A. Gingras,et al.  Beyond hairballs: The use of quantitative mass spectrometry data to understand protein–protein interactions , 2012, FEBS letters.

[2]  Ronald C. Petersen,et al.  Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease , 2009, Alzheimer's & Dementia.

[3]  Thomas W. Mühleisen,et al.  Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease , 2013, Nature Genetics.

[4]  B. Dickson,et al.  A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila , 2007, Nature.

[5]  Martin Vingron,et al.  A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk , 2010, Nature.

[6]  R. Takahashi,et al.  A Product of the Human Gene Adjacent to parkin Is a Component of Lewy Bodies and Suppresses Pael Receptor-induced Cell Death* , 2003, Journal of Biological Chemistry.

[7]  A. Smith,et al.  Cerebral Subcortical Small Vessel Disease in Subjects With Pathologically Confirmed Alzheimer Disease: A Clinicopathologic Study in the Oxford Project to Investigate Memory and Ageing (OPTIMA) , 2014, Alzheimer disease and associated disorders.

[8]  A. Bateman,et al.  Protein interactions in human genetic diseases , 2008, Genome Biology.

[9]  H. Zoghbi,et al.  Interaction of Akt-Phosphorylated Ataxin-1 with 14-3-3 Mediates Neurodegeneration in Spinocerebellar Ataxia Type 1 , 2003, Cell.

[10]  J. Olson,et al.  Huntingtin Interacting Proteins Are Genetic Modifiers of Neurodegeneration , 2007, PLoS genetics.

[11]  M. Mann,et al.  Software Lock Mass by Two-Dimensional Minimization of Peptide Mass Errors , 2011, Journal of the American Society for Mass Spectrometry.

[12]  H. Paulson,et al.  Polyglutamine neurodegeneration: protein misfolding revisited , 2008, Trends in Neurosciences.

[13]  D. Min,et al.  Beta-amyloid precursor protein is a direct cleavage target of HtrA2 serine protease. Implications for the physiological function of HtrA2 in the mitochondria. , 2006, The Journal of biological chemistry.

[14]  Søren Brunak,et al.  Annotation of loci from genome-wide association studies using tissue-specific quantitative interaction proteomics , 2014, Nature Methods.

[15]  H. Erdjument-Bromage,et al.  LRPPRC is necessary for polyadenylation and coordination of translation of mitochondrial mRNAs , 2012, The EMBO journal.

[16]  Shreyasi Chatterjee,et al.  Dissociation of tau toxicity and phosphorylation: role of GSK-3β, MARK and Cdk5 in a Drosophila model , 2008, Human molecular genetics.

[17]  Marit Holden,et al.  GSEA-SNP: applying gene set enrichment analysis to SNP data from genome-wide association studies , 2008, Bioinform..

[18]  P. S. St George-Hyslop,et al.  Mature Glycosylation and Trafficking of Nicastrin Modulate Its Binding to Presenilins* 210 , 2002, The Journal of Biological Chemistry.

[19]  Matthias Mann,et al.  High confidence determination of specific protein-protein interactions using quantitative mass spectrometry. , 2008, Current opinion in biotechnology.

[20]  Ruedi Aebersold,et al.  Quantitative interaction proteomics using mass spectrometry , 2009, Nature Methods.

[21]  U. Landegren,et al.  Direct observation of individual endogenous protein complexes in situ by proximity ligation , 2006, Nature Methods.

[22]  J. Rioux.  International Inflammatory Bowel Disease Genetics Consortium Identifies >50 Genetic Risk Factors for Ulcerative Colitis , 2010 .

[23]  R. Aebersold,et al.  Analysis of protein complexes using mass spectrometry , 2007, Nature Reviews Molecular Cell Biology.

[24]  Effat S. Emamian,et al.  Serine 776 of Ataxin-1 Is Critical for Polyglutamine-Induced Disease in SCA1 Transgenic Mice , 2003, Neuron.

[25]  J. Y. Choi,et al.  Co-chaperone CHIP promotes aggregation of ataxin-1 , 2007, Molecular and Cellular Neuroscience.

[26]  M. Mann,et al.  Stop and go extraction tips for matrix-assisted laser desorption/ionization, nanoelectrospray, and LC/MS sample pretreatment in proteomics. , 2003, Analytical chemistry.

[27]  B. Winblad,et al.  A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N–terminus of β–amyloid , 1992, Nature Genetics.

[28]  M. Farrer,et al.  Genetics and genomics of Parkinson’s disease , 2014, Genome Medicine.

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

[30]  F. LaFerla,et al.  Alzheimer's disease. , 2010, The New England journal of medicine.

[31]  D. Chan,et al.  Analysis of the Human Endogenous Coregulator Complexome , 2011, Cell.

[32]  F. Sterky,et al.  LRPPRC is a mitochondrial matrix protein that is conserved in metazoans. , 2010, Biochemical and biophysical research communications.

[33]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[34]  J. Schulz,et al.  Large-Scale Screen for Modifiers of Ataxin-3-Derived Polyglutamine-Induced Toxicity in Drosophila , 2012, PloS one.

[35]  C. Haass,et al.  Neurotoxic Mechanisms Caused by the Alzheimer's Disease-linked Swedish Amyloid Precursor Protein Mutation , 2003, Journal of Biological Chemistry.

[36]  M. Beal,et al.  Alzheimer's APP mangles mitochondria , 2006, Nature Medicine.

[37]  C. Shaw,et al.  Partial Loss of Ataxin-1 Function Contributes to Transcriptional Dysregulation in Spinocerebellar Ataxia Type 1 Pathogenesis , 2010, PLoS genetics.

[38]  Eva Syková,et al.  Department of Neuroscience , 2009 .

[39]  A. J. Slater,et al.  Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. , 2008, Archives of neurology.

[40]  V. Mootha,et al.  Mitochondrial and Nuclear Genomic Responses to Loss of LRPPRC Expression* , 2010, The Journal of Biological Chemistry.

[41]  D. Selkoe,et al.  Complex N-linked Glycosylated Nicastrin Associates with Active γ-Secretase and Undergoes Tight Cellular Regulation* , 2002, The Journal of Biological Chemistry.

[42]  C Hulette,et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) , 1995, Neurology.

[43]  K. Tanaka,et al.  VCP/p97 in abnormal protein aggregates, cytoplasmic vacuoles, and cell death, phenotypes relevant to neurodegeneration , 2001, Cell Death and Differentiation.

[44]  Matthias Selbach,et al.  Analyzing protein-protein interactions by quantitative mass spectrometry. , 2011, Methods.

[45]  R. Sharan,et al.  Protein networks in disease. , 2008, Genome research.

[46]  Jürgen Cox,et al.  A practical guide to the MaxQuant computational platform for SILAC-based quantitative proteomics , 2009, Nature Protocols.

[47]  C. Ross,et al.  Protein aggregation and neurodegenerative disease , 2004, Nature Medicine.

[48]  R. Tanzi,et al.  Twenty Years of the Alzheimer’s Disease Amyloid Hypothesis: A Genetic Perspective , 2005, Cell.

[49]  H. Zoghbi,et al.  Identification of genes that modify ataxin-1-induced neurodegeneration , 2000, Nature.

[50]  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.

[51]  Lukas N. Mueller,et al.  An integrated mass spectrometric and computational framework for the analysis of protein interaction networks , 2007, Nature Biotechnology.

[52]  Anton J. Enright,et al.  Network visualization and analysis of gene expression data using BioLayout Express3D , 2009, Nature Protocols.

[53]  E. Shoubridge,et al.  LRPPRC and SLIRP Interact in a Ribonucleoprotein Complex That Regulates Posttranscriptional Gene Expression in Mitochondria , 2010, Molecular biology of the cell.

[54]  H. Zoghbi,et al.  Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I , 1993, Nature Genetics.

[55]  S. L. Wong,et al.  Towards a proteome-scale map of the human protein–protein interaction network , 2005, Nature.

[56]  A. Barabasi,et al.  Network medicine : a network-based approach to human disease , 2010 .

[57]  H. Anandatheerthavarada,et al.  Mitochondrial trafficking of APP and alpha synuclein: Relevance to mitochondrial dysfunction in Alzheimer's and Parkinson's diseases. , 2010, Biochimica et biophysica acta.

[58]  Janghoo Lim,et al.  ATAXIN-1 Interacts with the Repressor Capicua in Its Native Complex to Cause SCA1 Neuropathology , 2006, Cell.

[59]  R. Murray,et al.  Familiality of clinical characteristics in schizophrenia. , 2002, Journal of psychiatric research.

[60]  C. Haass,et al.  Amyloid β-induced Changes in Nitric Oxide Production and Mitochondrial Activity Lead to Apoptosis* , 2004, Journal of Biological Chemistry.

[61]  Eric S. Lander,et al.  Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[62]  A. Barabasi,et al.  Interactome Networks and Human Disease , 2011, Cell.

[63]  M. Mann,et al.  Andromeda: a peptide search engine integrated into the MaxQuant environment. , 2011, Journal of proteome research.

[64]  M. Moran,et al.  Large-scale mapping of human protein–protein interactions by mass spectrometry , 2007, Molecular systems biology.

[65]  D. Galati,et al.  Accumulation of Amyloid Precursor Protein in the Mitochondrial Import Channels of Human Alzheimer’s Disease Brain Is Associated with Mitochondrial Dysfunction , 2006, The Journal of Neuroscience.

[66]  M. Robin,et al.  Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells , 2003, The Journal of cell biology.

[67]  P. R. Gardner.  Aconitase: sensitive target and measure of superoxide. , 2002, Methods in enzymology.

[68]  P S Harper,et al.  Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats. , 1996, American journal of human genetics.

[69]  M. Vidal,et al.  Edgetic perturbation models of human inherited disorders , 2009, Molecular systems biology.

[70]  R. Brent,et al.  Correlation of two-hybrid affinity data with in vitro measurements , 1995, Molecular and cellular biology.

[71]  M. Daly,et al.  Proteins Encoded in Genomic Regions Associated with Immune-Mediated Disease Physically Interact and Suggest Underlying Biology , 2011, PLoS genetics.

[72]  M. Mann,et al.  MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification , 2008, Nature Biotechnology.

[73]  A. Venter,et al.  Journal of The American Society for Mass Spectrometry , 2005, Journal of the American Society for Mass Spectrometry.

[74]  Thomas E. Nichols,et al.  Anatomically-distinct genetic associations of APOE ɛ4 allele load with regional cortical atrophy in Alzheimer's disease , 2009, NeuroImage.

[75]  Janghoo Lim,et al.  Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1 , 2008, Nature.

[76]  H. Lehrach,et al.  A Human Protein-Protein Interaction Network: A Resource for Annotating the Proteome , 2005, Cell.

[77]  Julian Mintseris,et al.  A Protein Complex Network of Drosophila melanogaster , 2011, Cell.