SpringerLink
Log in

Wolframin is a novel regulator of tau pathology and neurodegeneration

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Selective neuronal vulnerability to protein aggregation is found in many neurodegenerative diseases including Alzheimer’s disease (AD). Understanding the molecular origins of this selective vulnerability is, therefore, of fundamental importance. Tau protein aggregates have been found in Wolframin (WFS1)-expressing excitatory neurons in the entorhinal cortex, one of the earliest affected regions in AD. The role of WFS1 in Tauopathies and its levels in tau pathology-associated neurodegeneration, however, is largely unknown. Here we report that WFS1 deficiency is associated with increased tau pathology and neurodegeneration, whereas overexpression of WFS1 reduces those changes. We also find that WFS1 interacts with tau protein and controls the susceptibility to tau pathology. Furthermore, chronic ER stress and autophagy-lysosome pathway (ALP)-associated genes are enriched in WFS1-high excitatory neurons in human AD at early Braak stages. The protein levels of ER stress and autophagy-lysosome pathway (ALP)-associated proteins are changed in tau transgenic mice with WFS1 deficiency, while overexpression of WFS1 reverses those changes. This work demonstrates a possible role for WFS1 in the regulation of tau pathology and neurodegeneration via chronic ER stress and the downstream ALP. Our findings provide insights into mechanisms that underpin selective neuronal vulnerability, and for develo** new therapeutics to protect vulnerable neurons in AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Abisambra JF, **wal UK, Blair LJ, O’Leary JC 3rd, Li Q, Brady S et al (2013) Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation. J Neurosci 33:9498–9507. https://doi.org/10.1523/JNEUROSCI.5397-12.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T et al (2015) Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 18:1584–1593. https://doi.org/10.1038/nn.4132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Beach TG, Adler CH, Sue LI, Serrano G, Shill HA, Walker DG et al (2015) Arizona study of aging and neurodegenerative disorders and brain and body donation program. Neuropathology 35:354–389. https://doi.org/10.1111/neup.12189

    Article  PubMed  PubMed Central  Google Scholar 

  4. Boland B, Yu WH, Corti O, Mollereau B, Henriques A, Bezard E et al (2018) Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing. Nat Rev Drug Discov 17:660–688. https://doi.org/10.1038/nrd.2018.109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bolos M, Llorens-Martin M, Jurado-Arjona J, Hernandez F, Rabano A, Avila J (2016) Direct evidence of internalization of tau by microglia in vitro and in vivo. J Alzheimers Dis 50:77–87. https://doi.org/10.3233/JAD-150704

    Article  CAS  PubMed  Google Scholar 

  6. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259. https://doi.org/10.1007/BF00308809

    Article  CAS  PubMed  Google Scholar 

  7. Cagalinec M, Liiv M, Hodurova Z, Hickey MA, Vaarmann A, Mandel M et al (2016) Role of mitochondrial dynamics in neuronal development: mechanism for Wolfram syndrome. PLoS Biol 14:e1002511. https://doi.org/10.1371/journal.pbio.1002511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen S, Chang Y, Li L, Acosta D, Morrison C, Wang C et al (2021) Spatially resolved transcriptomics reveals unique gene signatures associated with human temporal cortical architecture and Alzheimer’s pathology. bioRxiv. https://doi.org/10.1101/2021.07.07.451554

    Article  PubMed  PubMed Central  Google Scholar 

  9. Chen WT, Lu A, Craessaerts K, Pavie B, Sala Frigerio C, Corthout N et al (2020) Spatial transcriptomics and in situ sequencing to study Alzheimer’s disease. Cell 182(976–991):e919. https://doi.org/10.1016/j.cell.2020.06.038

    Article  CAS  Google Scholar 

  10. Cortes CJ, La Spada AR (2019) TFEB dysregulation as a driver of autophagy dysfunction in neurodegenerative disease: molecular mechanisms, cellular processes, and emerging therapeutic opportunities. Neurobiol Dis 122:83–93. https://doi.org/10.1016/j.nbd.2018.05.012

    Article  CAS  PubMed  Google Scholar 

  11. de Calignon A, Polydoro M, Suarez-Calvet M, William C, Adamowicz DH, Kopeikina KJ et al (2012) Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73:685–697. https://doi.org/10.1016/j.neuron.2011.11.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Delpech JC, Pathak D, Varghese M, Kalavai SV, Hays EC, Hof PR et al (2021) Wolframin-1-expressing neurons in the entorhinal cortex propagate tau to CA1 neurons and impair hippocampal memory in mice. Sci Transl Med 13:eabe8455. https://doi.org/10.1126/scitranslmed.abe8455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fisher DW, Bennett DA, Dong H (2018) Sexual dimorphism in predisposition to Alzheimer’s disease. Neurobiol Aging 70:308–324. https://doi.org/10.1016/j.neurobiolaging.2018.04.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fonseca SG, Fukuma M, Lipson KL, Nguyen LX, Allen JR, Oka Y et al (2005) WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. J Biol Chem 280:39609–39615. https://doi.org/10.1074/jbc.M507426200

    Article  CAS  PubMed  Google Scholar 

  15. Fonseca SG, Ishigaki S, Oslowski CM, Lu S, Lipson KL, Ghosh R et al (2010) Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J Clin Invest 120:744–755. https://doi.org/10.1172/JCI39678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fredriksson S, Gullberg M, Jarvius J, Olsson C, Pietras K, Gustafsdottir SM et al (2002) Protein detection using proximity-dependent DNA ligation assays. Nat Biotechnol 20:473–477. https://doi.org/10.1038/nbt0502-473

    Article  CAS  PubMed  Google Scholar 

  17. Fu H, Hardy J, Duff KE (2018) Selective vulnerability in neurodegenerative diseases. Nat Neurosci 21:1350–1358. https://doi.org/10.1038/s41593-018-0221-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fu H, Hussaini SA, Wegmann S, Profaci C, Daniels JD, Herman M et al (2016) 3D visualization of the temporal and spatial spread of tau pathology reveals extensive sites of tau accumulation associated with neuronal loss and recognition memory deficit in aged tau transgenic mice. PLoS ONE 11:e0159463. https://doi.org/10.1371/journal.pone.0159463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fu H, Possenti A, Freer R, Nakano Y, Hernandez Villegas NC, Tang M et al (2019) A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology. Nat Neurosci 22:47–56. https://doi.org/10.1038/s41593-018-0298-7

    Article  CAS  PubMed  Google Scholar 

  20. Fu H, Rodriguez GA, Herman M, Emrani S, Nahmani E, Barrett G et al (2017) Tau pathology induces excitatory neuron loss, grid cell dysfunction, and spatial memory deficits reminiscent of early Alzheimer’s disease. Neuron 93(533–541):e535. https://doi.org/10.1016/j.neuron.2016.12.023

    Article  CAS  Google Scholar 

  21. Fujita E, Kouroku Y, Isoai A, Kumagai H, Misutani A, Matsuda C et al (2007) Two endoplasmic reticulum-associated degradation (ERAD) systems for the novel variant of the mutant dysferlin: ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II). Hum Mol Genet 16:618–629. https://doi.org/10.1093/hmg/ddm002

    Article  CAS  PubMed  Google Scholar 

  22. Grubman A, Chew G, Ouyang JF, Sun G, Choo XY, McLean C et al (2019) A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation. Nat Neurosci 22:2087–2097. https://doi.org/10.1038/s41593-019-0539-4

    Article  CAS  PubMed  Google Scholar 

  23. Guo JL, Narasimhan S, Changolkar L, He Z, Stieber A, Zhang B et al (2016) Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice. J Exp Med 213:2635–2654. https://doi.org/10.1084/jem.20160833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Halliday M, Radford H, Zents KAM, Molloy C, Moreno JA, Verity NC et al (2017) Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain 140:1768–1783. https://doi.org/10.1093/brain/awx074

    Article  PubMed  PubMed Central  Google Scholar 

  25. Hetz C, Mollereau B (2014) Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat Rev Neurosci 15:233–249. https://doi.org/10.1038/nrn3689

    Article  CAS  PubMed  Google Scholar 

  26. Iba M, McBride JD, Guo JL, Zhang B, Trojanowski JQ, Lee VM (2015) Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC’s afferent and efferent connections. Acta Neuropathol 130:349–362. https://doi.org/10.1007/s00401-015-1458-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ivask M, Hugill A, Koks S (2016) RNA-sequencing of WFS1-deficient pancreatic islets. Physiol Rep. https://doi.org/10.14814/phy2.12750

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ivask M, Volke V, Raasmaja A, Koks S (2021) High-fat diet associated sensitization to metabolic stress in Wfs1 heterozygous mice. Mol Genet Metab 134:203–211. https://doi.org/10.1016/j.ymgme.2021.07.002

    Article  CAS  PubMed  Google Scholar 

  29. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB et al (2018) NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement 14:535–562. https://doi.org/10.1016/j.jalz.2018.02.018

    Article  PubMed  PubMed Central  Google Scholar 

  30. Jack CR Jr, Holtzman DM (2013) Biomarker modeling of Alzheimer’s disease. Neuron 80:1347–1358. https://doi.org/10.1016/j.neuron.2013.12.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jack CR Jr, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS et al (2013) Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 12:207–216. https://doi.org/10.1016/S1474-4422(12)70291-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jicha GA, Bowser R, Kazam IG, Davies P (1997) Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau. J Neurosci Res 48:128–132. https://doi.org/10.1002/(sici)1097-4547(19970415)48:2%3c128::aid-jnr5%3e3.0.co;2-e

    Article  CAS  PubMed  Google Scholar 

  33. Jucker M, Walker LC (2018) Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases. Nat Neurosci 21:1341–1349. https://doi.org/10.1038/s41593-018-0238-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kakiuchi C, Ishiwata M, Hayashi A, Kato T (2006) XBP1 induces WFS1 through an endoplasmic reticulum stress response element-like motif in SH-SY5Y cells. J Neurochem 97:545–555. https://doi.org/10.1111/j.1471-4159.2006.03772.x

    Article  CAS  PubMed  Google Scholar 

  35. Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10:698–712. https://doi.org/10.1038/nrd3505

    Article  CAS  PubMed  Google Scholar 

  36. Kawano J, Fu**aga R, Yamamoto-Hanada K, Oka Y, Tanizawa Y, Shinoda K (2009) Wolfram syndrome 1 (Wfs1) mRNA expression in the normal mouse brain during postnatal development. Neurosci Res 64:213–230. https://doi.org/10.1016/j.neures.2009.03.005

    Article  CAS  PubMed  Google Scholar 

  37. Kitamura T (2017) Driving and regulating temporal association learning coordinated by entorhinal-hippocampal network. Neurosci Res 121:1–6. https://doi.org/10.1016/j.neures.2017.04.005

    Article  PubMed  Google Scholar 

  38. Kitamura T, Pignatelli M, Suh J, Kohara K, Yoshiki A, Abe K et al (2014) Island cells control temporal association memory. Science 343:896–901. https://doi.org/10.1126/science.1244634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Koks S, Soomets U, Paya-Cano JL, Fernandes C, Luuk H, Plaas M et al (2009) Wfs1 gene deletion causes growth retardation in mice and interferes with the growth hormone pathway. Physiol Genomics 37:249–259. https://doi.org/10.1152/physiolgenomics.90407.2008

    Article  CAS  PubMed  Google Scholar 

  40. Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z et al (2016) Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res 44:W90-97. https://doi.org/10.1093/nar/gkw377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lasagna-Reeves CA, de Haro M, Hao S, Park J, Rousseaux MW, Al-Ramahi I et al (2016) Reduction of Nuak1 decreases tau and reverses phenotypes in a tauopathy mouse model. Neuron 92:407–418. https://doi.org/10.1016/j.neuron.2016.09.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Leng K, Li E, Eser R, Piergies A, Sit R, Tan M et al (2021) Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease. Nat Neurosci 24:276–287. https://doi.org/10.1038/s41593-020-00764-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Li L, Venkataraman L, Chen S, Fu H (2020) Function of WFS1 and WFS2 in the central nervous system: implications for Wolfram syndrome and Alzheimer’s disease. Neurosci Biobehav Rev 118:775–783. https://doi.org/10.1016/j.neubiorev.2020.09.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lie PPY, Yang DS, Stavrides P, Goulbourne CN, Zheng P, Mohan PS et al (2021) Post-Golgi carriers, not lysosomes, confer lysosomal properties to pre-degradative organelles in normal and dystrophic axons. Cell Rep 35:109034. https://doi.org/10.1016/j.celrep.2021.109034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C et al (2012) Trans-synaptic spread of tau pathology in vivo. PLoS ONE 7:e31302. https://doi.org/10.1371/journal.pone.0031302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Martini-Stoica H, Cole AL, Swartzlander DB, Chen F, Wan YW, Bajaj L et al (2018) TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading. J Exp Med 215:2355–2377. https://doi.org/10.1084/jem.20172158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Martini-Stoica H, Xu Y, Ballabio A, Zheng H (2016) The autophagy-lysosomal pathway in neurodegeneration: a TFEB perspective. Trends Neurosci 39:221–234. https://doi.org/10.1016/j.tins.2016.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ et al (2019) Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570:332–337. https://doi.org/10.1038/s41586-019-1195-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Meier S, Bell M, Lyons DN, Ingram A, Chen J, Gensel JC et al (2015) Identification of novel tau interactions with endoplasmic reticulum proteins in Alzheimer’s disease brain. J Alzheimers Dis 48:687–702. https://doi.org/10.3233/JAD-150298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Menzies FM, Fleming A, Rubinsztein DC (2015) Compromised autophagy and neurodegenerative diseases. Nat Rev Neurosci 16:345–357. https://doi.org/10.1038/nrn3961

    Article  CAS  PubMed  Google Scholar 

  51. Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW et al (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 123:1–11. https://doi.org/10.1007/s00401-011-0910-3

    Article  CAS  PubMed  Google Scholar 

  52. Morrison JH, Hof PR (2007) Life and death of neurons in the aging cerebral cortex. Int Rev Neurobiol 81:41–57. https://doi.org/10.1016/S0074-7742(06)81004-4

    Article  CAS  PubMed  Google Scholar 

  53. Morrison JH, Hof PR (2002) Selective vulnerability of corticocortical and hippocampal circuits in aging and Alzheimer’s disease. Prog Brain Res 136:467–486. https://doi.org/10.1016/s0079-6123(02)36039-4

    Article  CAS  PubMed  Google Scholar 

  54. Moser EI, Kropff E, Moser MB (2008) Place cells, grid cells, and the brain’s spatial representation system. Annu Rev Neurosci 31:69–89. https://doi.org/10.1146/annurev.neuro.31.061307.090723

    Article  CAS  PubMed  Google Scholar 

  55. Nakashima A, Cheng SB, Kusabiraki T, Motomura K, Aoki A, Ushijima A et al (2019) Endoplasmic reticulum stress disrupts lysosomal homeostasis and induces blockade of autophagic flux in human trophoblasts. Sci Rep 9:11466. https://doi.org/10.1038/s41598-019-47607-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Narasimhan S, Guo JL, Changolkar L, Stieber A, McBride JD, Silva LV et al (2017) Pathological tau strains from human brains recapitulate the diversity of tauopathies in nontransgenic mouse brain. J Neurosci 37:11406–11423. https://doi.org/10.1523/JNEUROSCI.1230-17.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Radford H, Moreno JA, Verity N, Halliday M, Mallucci GR (2015) PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia. Acta Neuropathol 130:633–642. https://doi.org/10.1007/s00401-015-1487-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rashid HO, Yadav RK, Kim HR, Chae HJ (2015) ER stress: autophagy induction, inhibition and selection. Autophagy 11:1956–1977. https://doi.org/10.1080/15548627.2015.1091141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rauch JN, Luna G, Guzman E, Audouard M, Challis C, Sibih YE et al (2020) LRP1 is a master regulator of tau uptake and spread. Nature 580:381–385. https://doi.org/10.1038/s41586-020-2156-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Riggs AC, Bernal-Mizrachi E, Ohsugi M, Wasson J, Fatrai S, Welling C et al (2005) Mice conditionally lacking the Wolfram gene in pancreatic islet beta cells exhibit diabetes as a result of enhanced endoplasmic reticulum stress and apoptosis. Diabetologia 48:2313–2321. https://doi.org/10.1007/s00125-005-1947-4

    Article  CAS  PubMed  Google Scholar 

  61. Sakakibara Y, Sekiya M, Fujisaki N, Quan X, Iijima KM (2018) Knockdown of wfs1, a fly homolog of Wolfram syndrome 1, in the nervous system increases susceptibility to age- and stress-induced neuronal dysfunction and degeneration in Drosophila. PLoS Genet 14:e1007196. https://doi.org/10.1371/journal.pgen.1007196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A et al (2014) Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82:1271–1288. https://doi.org/10.1016/j.neuron.2014.04.047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA et al (2009) A gene network regulating lysosomal biogenesis and function. Science 325:473–477. https://doi.org/10.1126/science.1174447

    Article  CAS  PubMed  Google Scholar 

  64. Scrivo A, Bourdenx M, Pampliega O, Cuervo AM (2018) Selective autophagy as a potential therapeutic target for neurodegenerative disorders. Lancet Neurol 17:802–815. https://doi.org/10.1016/S1474-4422(18)30238-2

    Article  PubMed  PubMed Central  Google Scholar 

  65. Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, Erdin S et al (2011) TFEB links autophagy to lysosomal biogenesis. Science 332:1429–1433. https://doi.org/10.1126/science.1204592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Stancu IC, Vasconcelos B, Terwel D, Dewachter I (2014) Models of beta-amyloid induced Tau-pathology: the long and “folded” road to understand the mechanism. Mol Neurodegener 9:51. https://doi.org/10.1186/1750-1326-9-51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Stranahan AM, Mattson MP (2010) Selective vulnerability of neurons in layer II of the entorhinal cortex during aging and Alzheimer’s disease. Neural Plast 2010:108190. https://doi.org/10.1155/2010/108190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Takeda K, Inoue H, Tanizawa Y, Matsuzaki Y, Oba J, Watanabe Y et al (2001) WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain. Hum Mol Genet 10:477–484. https://doi.org/10.1093/hmg/10.5.477

    Article  CAS  PubMed  Google Scholar 

  69. Terasmaa A, Soomets U, Oflijan J, Punapart M, Hansen M, Matto V et al (2011) Wfs1 mutation makes mice sensitive to insulin-like effect of acute valproic acid and resistant to streptozocin. J Physiol Biochem 67:381–390. https://doi.org/10.1007/s13105-011-0088-0

    Article  CAS  PubMed  Google Scholar 

  70. Urano F (2016) Wolfram syndrome: diagnosis, management, and treatment. Curr Diab Rep 16:6. https://doi.org/10.1007/s11892-015-0702-6

    Article  PubMed  PubMed Central  Google Scholar 

  71. Vonsattel JP, Del Amaya MP, Keller CE (2008) Twenty-first century brain banking. Processing brains for research: the Columbia University methods. Acta Neuropathol 115:509–532. https://doi.org/10.1007/s00401-007-0311-9

    Article  PubMed  Google Scholar 

  72. Xu Y, Du S, Marsh JA, Horie K, Sato C, Ballabio A et al (2020) TFEB regulates lysosomal exocytosis of tau and its loss of function exacerbates tau pathology and spreading. Mol Psychiatry. https://doi.org/10.1038/s41380-020-0738-0

    Article  PubMed  PubMed Central  Google Scholar 

  73. Yamada T, Ishihara H, Tamura A, Takahashi R, Yamaguchi S, Takei D et al (2006) WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. Hum Mol Genet 15:1600–1609. https://doi.org/10.1093/hmg/ddl081

    Article  CAS  PubMed  Google Scholar 

  74. Yamamoto A, Simonsen A (2011) The elimination of accumulated and aggregated proteins: a role for aggrephagy in neurodegeneration. Neurobiol Dis 43:17–28. https://doi.org/10.1016/j.nbd.2010.08.015

    Article  CAS  PubMed  Google Scholar 

  75. Yang DS, Lee JH, Nixon RA (2009) Monitoring autophagy in Alzheimer’s disease and related neurodegenerative diseases. Methods Enzymol 453:111–144. https://doi.org/10.1016/S0076-6879(08)04006-8

    Article  CAS  PubMed  Google Scholar 

  76. Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC et al (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337–351. https://doi.org/10.1016/j.neuron.2007.01.010

    Article  CAS  PubMed  Google Scholar 

  77. Yu G, Wang LG, Han Y, He QY (2012) clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16:284–287. https://doi.org/10.1089/omi.2011.0118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by awards K01-AG056673, R56-AG066782-01 and R01-AG075092-01 (H.F.) from the National Institute on Aging of the National Institutes of Health and the award R01-GM131399 (Q.M.) from the National Institute of General Medical Sciences. The work was also supported by the award of AARF-17-505009 (H.F.) from the Alzheimer’s Association, the W81XWH1910309 (H.F.) from the Department of Defense, and the 10x Genomics 2021 Neuroscience Challenge award. Neurobehavioral tests were performed in the Department of Neuroscience Rodent Behavioral Core at Ohio State University, which was supported by NINDS P30NS04578. Some images were taken in the Department of Neuroscience Image Core, which was supported by P30 NS104177. The MSD assay was performed by the Clinical Research Center Analytical & Development Lab at The Ohio State University supported by Award Number UL1TR002733 from the National Center for Advancing Translational Sciences. We sincerely thank Marc Diamond for sharing the RD-P301S-YFP lentivector and DS9 tau cell line, Peter Davies for providing MC1, PHF1, and DA9 tau antibodies, and University of Tartu for sharing the Wfs1 knockout mice. We also thank Drs. Gail V.W. Johnson, Wai Haung Yu, Eric Klann and Andrea Tedeschi for helpful discussion. We thank the 10x Genomics technical support team for helpful discussions. We also thank Amanda Toland, Pearlly Yan, Tom Liu, Jennifer Mele from the Ohio State University and Amy Wetzel from the Nationwide Children’s Hospital for hel** with the RNA quality control and the sequencing. The RNA quality control was performed at NCI subsidized shared resource supported by The Ohio State University Comprehensive Cancer Center and the National Institutes of Health under grant number P30 CA016058. We thank Michael Rose and Rebecca Davis at The Ohio State University for preparing the human brain samples. Human de-identified brain tissues were kindly provided by the Banner Sun Health Research Institute Brain and Body Donation Program, supported by NIH grants U24-NS072026 and P30-AG19610 (TGB), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research as well as the Buckeye Brain Bank and the Buckeye Biospecimen Repository at the Ohio State University, and the New York Brain Bank at Columbia University Irving Medical Center supported by the Taub Institute and NIH grants P50AG008702 and P30AG066462. This work used the high-performance computing infrastructure at the Ohio State University.

Author information

Author notes

  1. Nancy C. Hernandez Villegas

    Present address: Current address: Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA

  2. Diana Acosta and Liang** Li have contributed equally.

Authors and Affiliations

  1. Department of Neuroscience, The Ohio State University, Columbus, OH, USA

    Shuo Chen, Diana Acosta, Liang** Li, Jiawen Liang, Julie Fitzgerald, Cody Morrison, Lalitha Venkataraman, Min Wu, Olga N. Kokiko-Cochran, Phillip Popovich & Hongjun Fu

  2. Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USA

    Shuo Chen & Yuzhou Chang

  3. Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA

    Yuzhou Chang, Cankun Wang & Qin Ma

  4. Center for Dementia Research, The Nathan S. Kline Institute for Psychiatric Research, New York, NY, USA

    Chris N. Goulbourne

  5. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA

    Yoshi Nakano, Nancy C. Hernandez Villegas & Karen E. Duff

  6. Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, OH, USA

    Lalitha Venkataraman

  7. Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA

    Cris Brown & Fumihiko Urano

  8. Banner Sun Health Research Institute, Sun City, AZ, USA

    Geidy E. Serrano & Thomas G. Beach

  9. Department of Neurology, Center for Cognitive and Memory Disorders, Center for Neuromodulation, The Ohio State University, Columbus, OH, USA

    Erica Bell & Douglas W. Scharre

  10. Clinical Research Center, Clinical Trials Management Organization, The Ohio State University, Columbus, OH, USA

    Trina Wemlinger

  11. Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA

    Xena E. Flowers, Lawrence S. Honig & Jean Paul Vonsattel

  12. Department of Biological Chemistry & Pharmacology, The Ohio State University, Columbus, OH, USA

    Jeff Kuret

  13. Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia

    Sulev Kõks

  14. Perron Institute for Neurological and Translational Science, Perth, WA, Australia

    Sulev Kõks

  15. UK Dementia Research Institute, UCL Queen Square Institute of Neurology, London, UK

    Karen E. Duff

  16. Discovery Theme on Chronic Brain Injury, The Ohio State University, Columbus, OH, USA

    Hongjun Fu

Authors
  1. Shuo Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Diana Acosta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liang** Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiawen Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuzhou Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cankun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Julie Fitzgerald
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cody Morrison
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chris N. Goulbourne
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yoshi Nakano
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nancy C. Hernandez Villegas
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Lalitha Venkataraman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Cris Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Geidy E. Serrano
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Erica Bell
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Trina Wemlinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Min Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Olga N. Kokiko-Cochran
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Phillip Popovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Xena E. Flowers
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Lawrence S. Honig
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Jean Paul Vonsattel
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Douglas W. Scharre
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Thomas G. Beach
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Qin Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Jeff Kuret
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Sulev Kõks
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Fumihiko Urano
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Karen E. Duff
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Hongjun Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HF designed and supervised the study, discussed the results, and wrote the paper. SC, DA, LL, and JL designed and performed experiments and analyzed the data and helped write the paper. YC generated all the pipelines for analyzing the 10 × Genomics Visium datasets. CW performed the single-nucleus RNA-Seq analysis. JF and ONK performed the behavioral tests. CM helped with the imaging data analysis. CNG performed the immuno-electron microscopy. YN, NCHV, and LV took part in the pilot studies. CB and MW helped with the PCR. GES, EB, XEF, LSH, JPV, DWS, and TGB prepared and characterized the human brain samples. T.W. performed the MSD assay. PP, TGB, QM, JK, SK, FU, and KED discussed and edited this paper.

Corresponding author

Correspondence to Hongjun Fu.

Ethics declarations

Conflict of interest

All authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 2207 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, S., Acosta, D., Li, L. et al. Wolframin is a novel regulator of tau pathology and neurodegeneration. Acta Neuropathol 143, 547–569 (2022). https://doi.org/10.1007/s00401-022-02417-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-022-02417-4

Keywords

Search

Navigation