A rare genetic disorder provides insights into mechanisms of early-onset neurodegeneration

Xeroderma pigmentosum (XP) is characterized by defective repair of ultraviolet-radiation (UVR)-induced DNA damage. Patients have UVR hypersensitivity and increased skin cancer risk. Effective photoprotection has reduced childhood cancer-related deaths, but revealed adolescence-onset neurodegeneration, arising through unknown mechanisms. Here, we investigate XP neurodegeneration using pluripotent stem cells derived from XP patients and healthy relatives, performing functional multi-omics on samples during neuronal differentiation. We find endoplasmic reticulum stress is upregulated, preceded by oxidative stress, causing substantial 5',8-cyclopurine and 8-oxopurine DNA damage. Critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity improves phenotypes, albeit inadequately, implying that early detection/prevention strategies are necessary to produce clinically impactful outcomes. Thus, we develop an early detection assay predicting neurodegeneration in at-risk patients.

[1]  D. Holtzman,et al.  Hallmarks of neurodegenerative diseases , 2023, Cell.

[2]  W. Baumeister,et al.  Gel‐like inclusions of C‐terminal fragments of TDP‐43 sequester stalled proteasomes in neurons , 2022, EMBO reports.

[3]  Daniel J. Gaffney,et al.  Substantial somatic genomic variation and selection for BCOR mutations in human induced pluripotent stem cells , 2021, Nature Genetics.

[4]  J. Svejstrup,et al.  Transcription-coupled repair and the transcriptional response to UV-Irradiation. , 2021, DNA repair.

[5]  S. Horvath,et al.  Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients , 2021, Cell stem cell.

[6]  J. Hoeijmakers,et al.  The central role of DNA damage in the ageing process , 2021, Nature.

[7]  Katherine R. Smith,et al.  A systematic CRISPR screen defines mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage , 2021, Nature Cancer.

[8]  Michael A. Terzidis,et al.  On the relevance of hydroxyl radical to purine DNA damage , 2021, Free radical research.

[9]  J. Svejstrup,et al.  Causes and consequences of RNA polymerase II stalling during transcript elongation , 2020, Nature Reviews Molecular Cell Biology.

[10]  Andrea Degasperi,et al.  Author Correction: A practical framework and online tool for mutational signature analyses show intertissue variation and driver dependencies , 2020, Nature Cancer.

[11]  C. Coman,et al.  A multi-omics analysis reveals the unfolded protein response regulon and stress-induced resistance to folate-based antimetabolites , 2020, Nature Communications.

[12]  L. Eriksson,et al.  Oxygen Dependent Purine Lesions in Double-Stranded Oligodeoxynucleotides: Kinetic and Computational Studies Highlight the Mechanism for 5',8-Cyplopurine Formation. , 2020, Journal of the American Chemical Society.

[13]  S. Morganella,et al.  A practical framework and online tool for mutational signature analyses show intertissue variation and driver dependencies , 2020, Nature Cancer.

[14]  Nicholas E. Propson,et al.  Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease. , 2020, The Journal of clinical investigation.

[15]  E. Cuppen,et al.  The mutational impact of culturing human pluripotent and adult stem cells , 2018, Nature Communications.

[16]  E. Parlanti,et al.  Purine DNA Lesions at Different Oxygen Concentration in DNA Repair-Impaired Human Cells (EUE-siXPA) , 2019, Cells.

[17]  K. Bobrowski,et al.  New Insights into the Reaction Paths of Hydroxyl Radicals with Purine Moieties in DNA and Double-Stranded Oligodeoxynucleotides , 2019, Molecules.

[18]  Luwen Wang,et al.  TDP-43 proteinopathy and mitochondrial abnormalities in neurodegeneration , 2019, Molecular and Cellular Neuroscience.

[19]  S. Pääbo,et al.  Simultaneous precise editing of multiple genes in human cells , 2019, Nucleic acids research.

[20]  H. Nakane,et al.  High levels of oxidatively generated DNA damage 8,5'-cyclo-2'-deoxyadenosine accumulate in the brain tissues of xeroderma pigmentosum group A gene-knockout mice. , 2019, DNA repair.

[21]  N. Geacintov,et al.  5′,8-Cyclopurine Lesions in DNA Damage: Chemical, Analytical, Biological, and Diagnostic Significance , 2019, Cells.

[22]  Connor R Tiffany,et al.  omu, a Metabolomics Count Data Analysis Tool for Intuitive Figures and Convenient Metadata Collection , 2019, Microbiology Resource Announcements.

[23]  C. Nishigori,et al.  Characteristics of Xeroderma Pigmentosum in Japan: Lessons From Two Clinical Surveys and Measures for Patient Care , 2019, Photochemistry and photobiology.

[24]  F. Tuorto,et al.  Loss of Proteostasis Is a Pathomechanism in Cockayne Syndrome. , 2018, Cell reports.

[25]  David Jones,et al.  cgpCaVEManWrapper: Simple Execution of CaVEMan in Order to Detect Somatic Single Nucleotide Variants in NGS Data , 2016, Current protocols in bioinformatics.

[26]  P. Froguel,et al.  Endoplasmic Reticulum Stress Links Oxidative Stress to Impaired Pancreatic Beta-Cell Function Caused by Human Oxidized LDL , 2016, PloS one.

[27]  T. Misteli,et al.  Repression of the Antioxidant NRF2 Pathway in Premature Aging , 2016, Cell.

[28]  A. Bradley,et al.  Mutational History of a Human Cell Lineage from Somatic to Induced Pluripotent Stem Cells , 2016, PLoS genetics.

[29]  A. Lehmann,et al.  Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect , 2016, Proceedings of the National Academy of Sciences.

[30]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[31]  J. Hoeijmakers,et al.  Aging: not all DNA damage is equal. , 2014, Current opinion in genetics & development.

[32]  Sikandar G. Khan,et al.  Living with xeroderma pigmentosum: comprehensive photoprotection for highly photosensitive patients , 2014, Photodermatology, photoimmunology & photomedicine.

[33]  J. Weissman,et al.  Differential Scales of Protein Quality Control , 2014, Cell.

[34]  S. Broyde,et al.  Structural basis for the recognition of diastereomeric 5′,8-cyclo-2′-deoxypurine lesions by the human nucleotide excision repair system , 2014, Nucleic acids research.

[35]  Wei Shi,et al.  featureCounts: an efficient general purpose program for assigning sequence reads to genomic features , 2013, Bioinform..

[36]  A. Lehmann,et al.  Patients with xeroderma pigmentosum complementation groups C, E and V do not have abnormal sunburn reactions , 2013, The British journal of dermatology.

[37]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[38]  Gabriel C. Lander,et al.  Complete subunit architecture of the proteasome regulatory particle , 2011, Nature.

[39]  D. Ferrington,et al.  Immunoproteasomes: structure, function, and antigen presentation. , 2012, Progress in molecular biology and translational science.

[40]  A. Basu,et al.  Structure of (5'S)-8,5'-cyclo-2'-deoxyguanosine in DNA. , 2011, Journal of the American Chemical Society.

[41]  Sikandar G. Khan,et al.  Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair , 2010, Journal of Medical Genetics.

[42]  B. Gwag,et al.  Induction of the unfolded protein response and cell death pathway in Alzheimer's disease, but not in aged Tg2576 mice , 2010, Experimental & Molecular Medicine.

[43]  J. Hoeijmakers.  DNA damage, aging, and cancer. , 2009, The New England journal of medicine.

[44]  P. Walter,et al.  The unfolded protein response during prostate cancer development , 2009, Cancer and Metastasis Reviews.

[45]  S. Webb.  A Patient’s Journey : Xeroderma pigmentosum , 2008 .

[46]  V. O'shea,et al.  Base-excision repair of oxidative DNA damage , 2007, Nature.

[47]  P. J. Brooks,et al.  The case for 8,5′-cyclopurine-2′-deoxynucleosides as endogenous DNA lesions that cause neurodegeneration in xeroderma pigmentosum , 2007, Neuroscience.

[48]  G. Bernardi,et al.  Beneficial effects of rolipram in a quinolinic acid model of striatal excitotoxicity , 2007, Neurobiology of Disease.

[49]  M. Brostrom,et al.  Reversible phosphorylation of eukaryotic initiation factor 2α in response to endoplasmic reticular signaling , 1993, Molecular and Cellular Biochemistry.

[50]  B. Van Houten,et al.  Basal transcription defect discriminates between xeroderma pigmentosum and trichothiodystrophy in XPD patients. , 2003, Molecular cell.

[51]  B. Winblad,et al.  The antidepressant and antiinflammatory effects of rolipram in the central nervous system. , 2006, CNS drug reviews.

[52]  J. Hoeijmakers.  Genome maintenance mechanisms for preventing cancer , 2001, Nature.

[53]  R. Tarone,et al.  The Oxidative DNA Lesion 8,5′-(S)-Cyclo-2′-deoxyadenosine Is Repaired by the Nucleotide Excision Repair Pathway and Blocks Gene Expression in Mammalian Cells* , 2000, The Journal of Biological Chemistry.

[54]  Anne Bertolotti,et al.  Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response , 2000, Nature Cell Biology.

[55]  T. Lindahl,et al.  Removal of oxygen free-radical-induced 5',8-purine cyclodeoxynucleosides from DNA by the nucleotide excision-repair pathway in human cells. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[56]  K. Mori,et al.  Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. , 1999, Molecular biology of the cell.

[57]  M. Oda,et al.  Neurodegeneration in hereditary nucleotide repair disorders , 1999, Brain and Development.

[58]  D. Ron,et al.  Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase , 1999, Nature.

[59]  V. Bohr,et al.  Repair of Oxidative Damage to Nuclear and Mitochondrial DNA in Mammalian Cells* , 1997, The Journal of Biological Chemistry.

[60]  J. T. Reardon,et al.  In vitro repair of oxidative DNA damage by human nucleotide excision repair system: possible explanation for neurodegeneration in xeroderma pigmentosum patients. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[61]  M. Hochstrasser.  Ubiquitin-dependent protein degradation. , 1996, Annual review of genetics.

[62]  Peter Walter,et al.  Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase , 1993, Cell.

[63]  J. Sambrook,et al.  The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins , 1988, Nature.

[64]  K. Kraemer,et al.  Xeroderma Pigmentosum: Cutaneous, Ocular, and Neurologic Abnormalities in 830 Published Cases , 1987 .

[65]  D. Bootsma,et al.  Genetic heterogeneity of xeroderma pigmentosum demonstrated by somatic cell hybridization. , 1972, Nature: New biology.

[66]  J. Cleaver.  Defective Repair Replication of DNA in Xeroderma Pigmentosum , 1968, Nature.

[67]  T. M. Anderson.  Note of a Rare Form of Skin Disease: Xeroderma Pigmentosum , 1889, British medical journal.