Skip to main content

Advertisement

SpringerLink
Log in

The role of the integral type II transmembrane protein BRI2 in health and disease

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

BRI2 is a type II transmembrane protein ubiquitously expressed whose physiological function remains poorly understood. Although several recent important advances have substantially impacted on our understanding of BRI2 biology and function, providing valuable information for further studies on BRI2. These findings have contributed to a better understanding of BRI2 biology and the underlying signaling pathways involved. In turn, these might provide novel insights with respect to neurodegeneration processes inherent to BRI2-related pathologies, namely Familial British and Danish dementias, Alzheimer’s disease, ITM2B-related retinal dystrophy, and multiple sclerosis. In this review, we provided a state-of-the-art outline of BRI2 biology, both in physiological and pathological conditions, and discuss the proposed molecular underlying mechanisms. Overall, the BRI2 knowledge here reviewed is of extreme importance and may contribute to propose BRI2 and/or BRI2 proteolytic fragments as novel therapeutic targets for neurodegenerative diseases, such as Alzheimer’s disease.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

modified by N-glycosylation (N) and ubiquitination (K) at the sites indicated. B Schematic representation of BRI2 processing. BRI2 (immature BRI2 or imBRI2) is cleaved by a proprotein convertase, namely furin, to release a secreted C-terminal 23-residue peptide (BRI2-23). The remaining membrane-bound N-terminal fragment is the mature form of BRI2 (mBRI2). BRI2 undergoes an additional cleavage in its ectodomain exerted by ADAM10 which results in the secretion of a soluble peptide containing the BRICHOS domain (BRI2-BRICHOS) and in a membrane-bound N-terminal fragment (BRI2 NTF). The NTF is subsequently subjected to intramembrane proteolysis cleavage by the SPPL2/b, generating a small, secreted, BRI2 C-terminal peptide (BRI2CTF) and an intracellular domain (BRI2ICD)

Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

Not applicable.

Code availability

Not applicable.

References

  1. Holton JL, Lashley T, Ghiso J et al (2002) Familial Danish dementia: a novel form of cerebral amyloidosis associated with deposition of both amyloid-Dan and amyloid-beta. J Neuropathol Exp Neurol 61:254–267

    Article  CAS  Google Scholar 

  2. Vidal R, Calero M, Révész T et al (2001) Sequence, genomic structure and tissue expression of Human BRI3, a member of the BRI gene family. Gene 266:95–102

    Article  CAS  Google Scholar 

  3. Rostagno A, Tomidokoro Y, Lashley T et al (2005) Chromosome 13 dementias. Cell Mol Life Sci 62:1814–1825. https://doi.org/10.1007/s00018-005-5092-5

    Article  CAS  PubMed  Google Scholar 

  4. Pittois K, Wauters J, Bossuyt P et al (1999) Genomic organization and chromosomal localization of the Itm2a gene. Mamm Genome 10:54–56

    Article  CAS  Google Scholar 

  5. Deleersnijder W, Hong G, Cortvrindt R et al (1996) Isolation of markers for chondro-osteogenic differentiation using cDNA library subtraction. Molecular cloning and characterization of a gene belonging to a novel multigene family of integral membrane proteins. J Biol Chem 271:19475–19482

    Article  CAS  Google Scholar 

  6. Van den Plas D, Merregaert J (2004) In vitro studies on Itm2a reveal its involvement in early stages of the chondrogenic differentiation pathway. Biol Cell 96:463–470. https://doi.org/10.1016/j.biolcel.2004.04.007

    Article  CAS  PubMed  Google Scholar 

  7. Van den Plas D, Merregaert J (2004) Constitutive overexpression of the integral membrane protein Itm2A enhances myogenic differentiation of C2C12 cells. Cell Biol Int 28:199–207. https://doi.org/10.1016/j.cellbi.2003.11.019

    Article  CAS  PubMed  Google Scholar 

  8. Kirchner J, Bevan MJ (1999) ITM2A is induced during thymocyte selection and T cell activation and causes downregulation of CD8 when overexpressed in CD4(+)CD8(+) double positive thymocytes. J Exp Med 190:217–228

    Article  CAS  Google Scholar 

  9. Martins F (2017) Functional characterization of novel BRI2 and BRI3 complexes Retrieved from RIA. PhD thesis. The Institutional repository of the University of Aveiro. http://hdl.handle.net/10773/21229

  10. Vidal R, Frangione B, Rostagno A et al (1999) A stop-codon mutation in the BRI gene associated with familial British dementia. Nature 399:776–781. https://doi.org/10.1038/21637

    Article  CAS  PubMed  Google Scholar 

  11. Choi SC, Kim J, Kim TH et al (2001) Cloning and characterization of a type II integral transmembrane protein gene, Itm2c, that is highly expressed in the mouse brain. Mol Cells 12:391–397

    CAS  PubMed  Google Scholar 

  12. Akiyama H, Kondo H, Arai T et al (2004) Expression of BRI, the normal precursor of the amyloid protein of familial British dementia, in human brain. Acta Neuropathol 107:53–58. https://doi.org/10.1007/s00401-003-0783-1

    Article  CAS  PubMed  Google Scholar 

  13. Garringer HJ, Sammeta N, Oblak A et al (2017) Amyloid and intracellular accumulation of BRI2. Neurobiol Aging 52:90–97. https://doi.org/10.1016/j.neurobiolaging.2016.12.018

    Article  CAS  PubMed  Google Scholar 

  14. Del Campo M, Hoozemans JJM, Dekkers L-L et al (2014) BRI2-BRICHOS is increased in human amyloid plaques in early stages of Alzheimer’s disease. Neurobiol Aging 35:1596–1604. https://doi.org/10.1016/j.neurobiolaging.2014.01.007

    Article  CAS  PubMed  Google Scholar 

  15. Choi S-I, Vidal R, Frangione B, Levy E (2004) Axonal transport of British and Danish amyloid peptides via secretory vesicles. FASEB J 18:373–375. https://doi.org/10.1096/fj.03-0730fje

    Article  CAS  PubMed  Google Scholar 

  16. Martins F, Rebelo S, Santos M et al (2016) BRI2 and BRI3 are functionally distinct phosphoproteins. Cell Signal 28:130–144. https://doi.org/10.1016/j.cellsig.2015.10.012

    Article  CAS  PubMed  Google Scholar 

  17. Martin L, Fluhrer R, Reiss K et al (2008) Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b. J Biol Chem 283:1644–1652. https://doi.org/10.1074/jbc.M706661200

    Article  CAS  PubMed  Google Scholar 

  18. Kim SH, Wang R, Gordon DJ et al (1999) Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia. Nat Neurosci 2:984–988. https://doi.org/10.1038/14783

    Article  CAS  PubMed  Google Scholar 

  19. Matsuda S, Matsuda Y, Snapp EL, D’Adamio L (2011) Maturation of BRI2 generates a specific inhibitor that reduces APP processing at the plasma membrane and in endocytic vesicles. Neurobiol Aging 32:1400–1408. https://doi.org/10.1016/j.neurobiolaging.2009.08.005

    Article  CAS  PubMed  Google Scholar 

  20. Tsachaki M, Ghiso J, Efthimiopoulos S (2008) BRI2 as a central protein involved in neurodegeneration. Biotechnol J 3:1548–1554. https://doi.org/10.1002/biot.200800247

    Article  CAS  PubMed  Google Scholar 

  21. Martin L, Fluhrer R, Haass C (2009) Substrate requirements for SPPL2b-dependent regulated intramembrane proteolysis. J Biol Chem 284:5662–5670. https://doi.org/10.1074/jbc.M807485200

    Article  CAS  PubMed  Google Scholar 

  22. Schneppenheim J, Huttl S, Mentrup T et al (2014) The intramembrane proteases signal peptide peptidase-like 2a and 2b have distinct functions in vivo. Mol Cell Biol. https://doi.org/10.1128/mcb.00038-14

    Article  PubMed  PubMed Central  Google Scholar 

  23. Fluhrer R, Martin L, Klier B et al (2012) The α-helical content of the transmembrane domain of the British dementia protein-2 (Bri2) determines its processing by signal peptide peptidase-like 2b (SPPL2b). J Biol Chem 287:5156–5163. https://doi.org/10.1074/jbc.M111.328104

    Article  CAS  PubMed  Google Scholar 

  24. Mentrup T, Häsler R, Fluhrer R et al (2015) A cell-based assay reveals nuclear translocation of intracellular domains released by SPPL proteases. Traffic 16:871–892. https://doi.org/10.1111/tra.12287

    Article  CAS  PubMed  Google Scholar 

  25. Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284:770–776

    Article  CAS  Google Scholar 

  26. Rebelo S, Domingues SC, Santos M et al (2013) Identification of a novel complex AβPP:Fe65:PP1 that regulates AβPP Thr668 phosphorylation levels. J Alzheimers Dis 35:761–775. https://doi.org/10.3233/JAD-130095

    Article  CAS  PubMed  Google Scholar 

  27. Martins F, Serrano J, Muller T et al (2017) BRI2 processing and its neuritogenic role are modulated by protein phosphatase 1 complexing. J Cell Biochem 118:2752–2763. https://doi.org/10.1002/jcb.25925

    Article  CAS  PubMed  Google Scholar 

  28. Lashley T, Revesz T, Plant G et al (2008) Expression of BRI2 mRNA and protein in normal human brain and familial British dementia: its relevance to the pathogenesis of disease. Neuropathol Appl Neurobiol 34:492–505. https://doi.org/10.1111/j.1365-2990.2008.00935.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Del Campo M, Teunissen CE (2014) Role of BRI2 in dementia. J Alzheimers Dis 40:481–494. https://doi.org/10.3233/JAD-131364

    Article  CAS  PubMed  Google Scholar 

  30. Tsachaki M, Serlidaki D, Fetani A et al (2011) Glycosylation of BRI2 on asparagine 170 is involved in its trafficking to the cell surface but not in its processing by furin or ADAM10. Glycobiology 21:1382–1388. https://doi.org/10.1093/glycob/cwr097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ullrich S, Münch A, Neumann S et al (2010) The novel membrane protein TMEM59 modulates complex glycosylation, cell surface expression, and secretion of the amyloid precursor protein. J Biol Chem 285:20664–20674. https://doi.org/10.1074/jbc.M109.055608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Demirkan G, Yu K, Boylan JM et al (2011) Phosphoproteomic profiling of in vivo signaling in liver by the mammalian target of rapamycin complex 1 (mTORC1). PLoS ONE 6:e21729. https://doi.org/10.1371/journal.pone.0021729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sharma K, D’Souza RCJ, Tyanova S et al (2014) Ultradeep human phosphoproteome reveals a distinct regulatory nature of Tyr and Ser/Thr-based signaling. Cell Rep 8:1583–1594. https://doi.org/10.1016/j.celrep.2014.07.036

    Article  CAS  PubMed  Google Scholar 

  34. Wilhelm M, Schlegl J, Hahne H et al (2014) Mass-spectrometry-based draft of the human proteome. Nature 509:582–587. https://doi.org/10.1038/nature13319

    Article  CAS  PubMed  Google Scholar 

  35. Oliveira J, Costa M, De Almeida MSC et al (2017) Protein phosphorylation is a key mechanism in Alzheimer’s Disease. J Alzheimer’s Dis 58(4):953–978. https://doi.org/10.3233/JAD-170176

  36. Rebelo S, Vieira SI, Esselmann H et al (2007) Tyr687 dependent APP endocytosis and Abeta production. J Mol Neurosci. https://doi.org/10.1007/s12031-007-0001-z

    Article  PubMed  Google Scholar 

  37. Rebelo S, Vieira SI, Esselmann H et al (2007) Tyrosine 687 phosphorylated Alzheimer’s amyloid precursor protein is retained intracellularly and exhibits a decreased turnover rate. Neurodegener Dis. https://doi.org/10.1159/000101831

    Article  PubMed  Google Scholar 

  38. Vieira SI, Rebelo S, Domingues SC et al (2009) S655 phosphorylation enhances APP secretory traffic. Mol Cell Biochem 328:145–154. https://doi.org/10.1007/s11010-009-0084-7

    Article  CAS  PubMed  Google Scholar 

  39. Oliveira JM, Henriques AG, Martins F et al (2015) Amyloid-β modulates both AβPP and Tau phosphorylation. J Alzheimers Dis. https://doi.org/10.3233/JAD-142664

    Article  PubMed  Google Scholar 

  40. Udeshi ND, Mani DR, Eisenhaure T et al (2012) Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition. Mol Cell Proteomics 11:148–159. https://doi.org/10.1074/mcp.M111.016857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shi Y, Chan DW, Jung SY et al (2011) A data set of human endogenous protein ubiquitination sites. Mol Cell Proteomics 10(M110):002089. https://doi.org/10.1074/mcp.M110.002089

    Article  CAS  PubMed  Google Scholar 

  42. Ciechanover A (1994) The ubiquitin-proteasome proteolytic pathway. Cell 79:13–21

    Article  CAS  Google Scholar 

  43. Glickman MH, Ciechanover A (2002) The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82:373–428. https://doi.org/10.1152/physrev.00027.2001

    Article  CAS  PubMed  Google Scholar 

  44. Yasukawa T, Tsutsui A, Tomomori-Sato C et al (2020) NRBP1-containing CRL2/CRL4A regulates Amyloid β production by targeting BRI2 and BRI3 for degradation. Cell Rep. https://doi.org/10.1016/j.celrep.2020.02.059

    Article  PubMed  Google Scholar 

  45. Martins F, Marafona AM, Pereira CD et al (2018) Identification and characterization of the BRI2 interactome in the brain. Sci Rep. https://doi.org/10.1038/s41598-018-21453-3

    Article  PubMed  PubMed Central  Google Scholar 

  46. Tsachaki M, Ghiso J, Rostagno A, Efthimiopoulos S (2010) BRI2 homodimerizes with the involvement of intermolecular disulfide bonds. Neurobiol Aging 31:88–98. https://doi.org/10.1016/j.neurobiolaging.2008.03.004

    Article  CAS  PubMed  Google Scholar 

  47. Tamayev R, Giliberto L, Li W et al (2010) Memory deficits due to familial British dementia BRI2 mutation are caused by loss of BRI2 function rather than amyloidosis. J Neurosci 30:14915–14924. https://doi.org/10.1523/JNEUROSCI.3917-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Tamayev R, Matsuda S, Fà M et al (2010) Danish dementia mice suggest that loss of function and not the amyloid cascade causes synaptic plasticity and memory deficits. Proc Natl Acad Sci U S A 107:20822–20827. https://doi.org/10.1073/pnas.1011689107

    Article  PubMed  PubMed Central  Google Scholar 

  49. Béïque J-C, Andrade R (2003) PSD-95 regulates synaptic transmission and plasticity in rat cerebral cortex. J Physiol 546:859–867. https://doi.org/10.1113/jphysiol.2002.031369

    Article  CAS  PubMed  Google Scholar 

  50. El-Husseini AE, Schnell E, Chetkovich DM et al (2000) PSD-95 involvement in maturation of excitatory synapses. Science 290:1364–1368

    Article  CAS  Google Scholar 

  51. Niethammer M, Kim E, Sheng M (1996) Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases. J Neurosci 16:2157–2163

    Article  CAS  Google Scholar 

  52. Kornau HC, Schenker LT, Kennedy MB, Seeburg PH (1995) Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 269:1737–1740

    Article  CAS  Google Scholar 

  53. Vitale M, Renzone G, Matsuda S et al (2012) Proteomic characterization of a mouse model of familial Danish dementia. J Biomed Biotechnol 2012:728178. https://doi.org/10.1155/2012/728178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yao W, Yin T, Tambini MD, D’Adamio L (2019) The Familial dementia gene ITM2b/BRI2 facilitates glutamate transmission via both presynaptic and postsynaptic mechanisms. Sci Rep. https://doi.org/10.1038/s41598-019-41340-9

    Article  PubMed  PubMed Central  Google Scholar 

  55. Schwenk J, Pérez-Garci E, Schneider A et al (2016) Modular composition and dynamics of native GABAB receptors identified by high-resolution proteomics. Nat Neurosci. https://doi.org/10.1038/nn.4198

    Article  PubMed  Google Scholar 

  56. Dinamarca MC, Raveh A, Schneider A et al (2019) Complex formation of APP with GABA B receptors links axonal trafficking to amyloidogenic processing. Nat Commun. https://doi.org/10.1038/s41467-019-09164-3

    Article  PubMed  PubMed Central  Google Scholar 

  57. Fotinopoulou A, Tsachaki M, Vlavaki M et al (2005) BRI2 interacts with amyloid precursor protein (APP) and regulates amyloid beta (Abeta) production. J Biol Chem 280:30768–30772. https://doi.org/10.1074/jbc.C500231200

    Article  CAS  PubMed  Google Scholar 

  58. Matsuda S, Giliberto L, Matsuda Y et al (2005) The familial dementia BRI2 gene binds the Alzheimer gene amyloid-beta precursor protein and inhibits amyloid-beta production. J Biol Chem 280:28912–28916. https://doi.org/10.1074/jbc.C500217200

    Article  CAS  PubMed  Google Scholar 

  59. Matsuda S, Giliberto L, Matsuda Y et al (2008) BRI2 inhibits amyloid beta-peptide precursor protein processing by interfering with the docking of secretases to the substrate. J Neurosci 28:8668–8676. https://doi.org/10.1523/JNEUROSCI.2094-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Tsachaki M, Fotinopoulou A, Slavi N et al (2013) BRI2 interacts with BACE1 and reduces its cellular levels by reducing the levels of BACE1 mRNA and inducing its degradation through the lysosomal pathway. Curr Alzheimer Res 10:532–541

    Article  CAS  Google Scholar 

  61. Kim J, Miller VM, Levites Y et al (2008) BRI2 (ITM2b) inhibits Abeta deposition in vivo. J Neurosci 28:6030–6036. https://doi.org/10.1523/JNEUROSCI.0891-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Peng S, Fitzen M, Jörnvall H, Johansson J (2010) The extracellular domain of Bri2 (ITM2B) binds the ABri peptide (1–23) and amyloid beta-peptide (Abeta1-40): implications for Bri2 effects on processing of amyloid precursor protein and Abeta aggregation. Biochem Biophys Res Commun 393:356–361. https://doi.org/10.1016/j.bbrc.2009.12.122

    Article  CAS  PubMed  Google Scholar 

  63. Willander H, Presto J, Askarieh G et al (2012) BRICHOS domains efficiently delay fibrillation of amyloid β-peptide. J Biol Chem 287:31608–31617. https://doi.org/10.1074/jbc.M112.393157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kilger E, Buehler A, Woelfing H et al (2011) BRI2 protein regulates β-amyloid degradation by increasing levels of secreted insulin-degrading enzyme (IDE). J Biol Chem 286:37446–37457. https://doi.org/10.1074/jbc.M111.288373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Morelli L, Llovera RE, Alonso LG et al (2005) Insulin-degrading enzyme degrades amyloid peptides associated with British and Danish familial dementia. Biochem Biophys Res Commun. https://doi.org/10.1016/j.bbrc.2005.05.020

    Article  PubMed  Google Scholar 

  66. Fleischer A, Ayllón V, Dumoutier L et al (2002) Proapoptotic activity of ITM2B(s), a BH3-only protein induced upon IL-2-deprivation which interacts with Bcl-2. Oncogene 21:3181–3189. https://doi.org/10.1038/sj.onc.1205464

    Article  CAS  PubMed  Google Scholar 

  67. Fleischer A, Ayllon V, Rebollo A (2002) ITM2Bs regulates apoptosis by inducing loss of mitochondrial membrane potential. Eur J Immunol. https://doi.org/10.1002/1521-4141(200212)32:12%3c3498::AID-IMMU3498%3e3.0.CO;2-C

    Article  PubMed  Google Scholar 

  68. Fleischer A, Rebollo A (2004) Induction of p53-independent apoptosis by the BH3-only protein ITM2Bs. FEBS Lett. https://doi.org/10.1016/S0014-5793(03)01519-9

    Article  PubMed  Google Scholar 

  69. Rengaraj D, Gao F, Liang X-H, Yang Z-M (2007) Expression and regulation of type II integral membrane protein family members in mouse male reproductive tissues. Endocrine 31:193–201

    Article  CAS  Google Scholar 

  70. Rengaraj D, Liang XH, Gao F et al (2008) Differential expression and regulation of integral membrane protein 2b in rat male reproductive tissues. Asian J Androl. https://doi.org/10.1111/j.1745-7262.2008.00360.x

    Article  PubMed  Google Scholar 

  71. Han C, Park I, Lee B et al (2011) Identification of heat shock protein 5, calnexin and integral membrane protein 2B as Adam7-interacting membrane proteins in mouse sperm. J Cell Physiol 226:1186–1195. https://doi.org/10.1002/jcp.22444

    Article  CAS  PubMed  Google Scholar 

  72. Mandal AK, Mount DB (2019) Interaction between ITM2B and GLUT9 links Urate transport to neurodegenerative disorders. Front Physiol. https://doi.org/10.3389/fphys.2019.01323

    Article  PubMed  PubMed Central  Google Scholar 

  73. Davies MN, Verdi S, Burri A et al (2015) Generalised anxiety disorder—a twin study of genetic architecture, genome-wide association and differential gene expression. PLoS ONE. https://doi.org/10.1371/journal.pone.0134865

    Article  PubMed  PubMed Central  Google Scholar 

  74. Matsuda S, Senda T (2019) BRI2 as an anti-Alzheimer gene. Med Mol Morphol 52:1–7. https://doi.org/10.1007/s00795-018-0191-1

    Article  CAS  PubMed  Google Scholar 

  75. Dolfe L, Tambaro S, Tigro H et al (2018) The Bri2 and Bri3 BRICHOS domains interact differently with Aβ42 and Alzheimer Amyloid plaques. J Alzheimer’s Dis Reports. https://doi.org/10.3233/adr-170051

    Article  Google Scholar 

  76. Poska H, Haslbeck M, Kurudenkandy FR et al (2016) Dementia-related Bri2 BRICHOS is a versatile molecular chaperone that efficiently inhibits A 42 toxicity in Drosophila. Biochem J 473:3683–3704. https://doi.org/10.1042/BCJ20160277

    Article  CAS  PubMed  Google Scholar 

  77. Kim SH, Creemers JWM, Chu S et al (2002) Proteolytic processing of familial British dementia-associated BRI variants: evidence for enhanced intracellular accumulation of amyloidogenic peptides. J Biol Chem. https://doi.org/10.1074/jbc.M108739200

    Article  PubMed  Google Scholar 

  78. Ghiso JA, Holton J, Miravalle L et al (2001) Systemic amyloid deposits in familial British dementia. J Biol Chem 276:43909–43914. https://doi.org/10.1074/jbc.M105956200

    Article  CAS  PubMed  Google Scholar 

  79. Vidal R, Revesz T, Rostagno A et al (2000) A decamer duplication in the 3’ region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred. Proc Natl Acad Sci U S A 97:4920–4925. https://doi.org/10.1073/pnas.080076097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Plant GT, Révész T, Barnard RO et al (1990) Familial cerebral amyloid angiopathy with nonneuritic amyloid plaque formation. Brain 113:721–747

    Article  Google Scholar 

  81. Mead S, James-Galton M, Revesz T et al (2000) Familial British dementia with amyloid angiopathy: early clinical, neuropsychological and imaging findings. Brain 123:975–991

    Article  Google Scholar 

  82. Revesz T, Holton JL, Doshi B et al (1999) Cytoskeletal pathology in familial cerebral amyloid angiopathy (British type) with non-neuritic amyloid plaque formation. Acta Neuropathol 97:170–176

    Article  CAS  Google Scholar 

  83. Strömgren E, Dalby A, Dalby MA, Ranheim B (1970) Cataract, deafness, cerebellar ataxia, psychosis and dementia—a new syndrome. Acta Neurol Scand 46(Suppl 43):261–262

    PubMed  Google Scholar 

  84. Tomidokoro Y, Lashley T, Rostagno A et al (2005) Familial Danish dementia: co-existence of Danish and Alzheimer amyloid subunits (ADan AND A{beta}) in the absence of compact plaques. J Biol Chem 280:36883–36894. https://doi.org/10.1074/jbc.M504038200

    Article  CAS  PubMed  Google Scholar 

  85. El-Agnaf O, Gibson G, Lee M et al (2004) Properties of neurotoxic peptides related to the Bri gene. Protein Pept Lett 11:207–212

    Article  CAS  Google Scholar 

  86. Gibson G, Gunasekera N, Lee M et al (2004) Oligomerization and neurotoxicity of the amyloid ADan peptide implicated in familial Danish dementia. J Neurochem 88:281–290

    Article  CAS  Google Scholar 

  87. Rostagno A, Ghiso J (2008) Preamyloid lesions and cerebrovascular deposits in the mechanism of dementia: lessons from non-beta-amyloid cerebral amyloidosis. Neurodegener Dis 5:173–175. https://doi.org/10.1159/000113694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bradt BM, Kolb WP, Cooper NR (1998) Complement-dependent proinflammatory properties of the Alzheimer’s disease beta-peptide. J Exp Med 188:431–438

    Article  CAS  Google Scholar 

  89. Yin T, Yao W, Lemenze AD, D’Adamio L (2020) Danish and British dementia ITM2b/BRI2 mutations reduce BRI2 protein stability and impair glutamatergic synaptic transmission. J Biol Chem. https://doi.org/10.1074/jbc.RA120.015679

    Article  PubMed  PubMed Central  Google Scholar 

  90. Tamayev R, D’Adamio L (2012) Memory deficits of British dementia knock-in mice are prevented by Aβ-precursor protein haploinsufficiency. J Neurosci 32:5481–5485. https://doi.org/10.1523/JNEUROSCI.5193-11.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Tamayev R, Matsuda S, Giliberto L et al (2011) APP heterozygosity averts memory deficit in knockin mice expressing the Danish dementia BRI2 mutant. EMBO J 30:2501–2509. https://doi.org/10.1038/emboj.2011.161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Matsuda S, Tamayev R, D’Adamio L (2011) Increased AβPP processing in familial Danish dementia patients. J Alzheimers Dis 27:385–391. https://doi.org/10.3233/JAD-2011-110785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Biundo F, Ishiwari K, Del Prete D, D’Adamio L (2016) Deletion of the γ-secretase subunits Aph1B/C impairs memory and worsens the deficits of knock-in mice modeling the Alzheimer-like familial Danish dementia. Oncotarget 7:11923–11944. https://doi.org/10.18632/oncotarget.7389

    Article  PubMed  PubMed Central  Google Scholar 

  94. Garringer HJ, Murrell J, D’Adamio L et al (2010) Modeling familial British and Danish dementia. Brain Struct Funct 214:235–244. https://doi.org/10.1007/s00429-009-0221-9

    Article  PubMed  Google Scholar 

  95. Cantlon A, Frigerio CS, Walsh DM (2015) Lessons from a rare familial dementia: amyloid and beyond. J Park Dis Alzheimer’s Dis 2(1):12. https://doi.org/10.13188/2376-922x.1000009

    Article  Google Scholar 

  96. Chen WT, Lu A, Craessaerts K et al (2020) Spatial transcriptomics and in situ sequencing to study Alzheimer’s disease. Cell. https://doi.org/10.1016/j.cell.2020.06.038

    Article  PubMed  PubMed Central  Google Scholar 

  97. Del Campo M, Oliveira CR, Scheper W et al (2015) BRI2 ectodomain affects Aβ42 fibrillation and tau truncation in human neuroblastoma cells. Cell Mol Life Sci 72:1599–1611. https://doi.org/10.1007/s00018-014-1769-y

    Article  CAS  PubMed  Google Scholar 

  98. Beers MF, Lomax CA, Russo SJ (1998) Synthetic processing of surfactant protein C by alevolar epithelial cells: the COOH terminus of proSP-C is required for post-translational targeting and proteolysis. J Biol Chem. https://doi.org/10.1074/jbc.273.24.15287

    Article  PubMed  Google Scholar 

  99. Sánchez-Pulido L, Devos D, Valencia A (2002) BRICHOS: a conserved domain in proteins associated with dementia, respiratory distress and cancer. Trends Biochem Sci 27:329–332

    Article  Google Scholar 

  100. Hedlund J, Johansson J, Persson B (2009) BRICHOS—a superfamily of multidomain proteins with diverse functions. BMC Res Notes. https://doi.org/10.1186/1756-0500-2-180

    Article  PubMed  PubMed Central  Google Scholar 

  101. Knight SD, Presto J, Linse S, Johansson J (2013) The BRICHOS domain, amyloid fibril formation, and their relationship. Biochemistry 52:7523–7531. https://doi.org/10.1021/bi400908x

    Article  CAS  PubMed  Google Scholar 

  102. Willander H, Hermansson E, Johansson J, Presto J (2011) BRICHOS domain associated with lung fibrosis, dementia and cancer—a chaperone that prevents amyloid fibril formation? FEBS J 278:3893–3904

    Article  CAS  Google Scholar 

  103. Cohen SIA, Arosio P, Presto J et al (2015) A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers. Nat Struct Mol Biol. https://doi.org/10.1038/nsmb.2971

    Article  PubMed  PubMed Central  Google Scholar 

  104. Chen G, Abelein A, Nilsson HE et al (2017) Bri2 BRICHOS client specificity and chaperone activity are governed by assembly state. Nat Commun 8:2081. https://doi.org/10.1038/s41467-017-02056-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Dolfe L, Winblad B, Johansson J, Presto J (2016) BRICHOS binds to a designed amyloid-forming β-protein and reduces proteasomal inhibition and aggresome formation. Biochem J. https://doi.org/10.1042/BJ20150920

    Article  PubMed  Google Scholar 

  106. Tambaro S, Galan-Acosta L, Leppert A et al (2019) Blood-brain and blood-cerebrospinal fluid passage of BRICHOS domains from two molecular chaperones in mice. J Biol Chem 294:2606–2615. https://doi.org/10.1074/jbc.RA118.004538

    Article  CAS  PubMed  Google Scholar 

  107. Galan-Acosta L, Sierra C, Leppert A et al (2020) Recombinant BRICHOS chaperone domains delivered to mouse brain parenchyma by focused ultrasound and microbubbles are internalized by hippocampal and cortical neurons. Mol Cell Neurosci. https://doi.org/10.1016/j.mcn.2020.103498

    Article  PubMed  Google Scholar 

  108. Audo I, Bujakowska K, Orhan E et al (2014) The familial dementia gene revisited: A missense mutation revealed by whole-exome sequencing identifies ITM2B as a candidate gene underlying a novel autosomal dominant retinal dystrophy in a large family. Hum Mol Genet. https://doi.org/10.1093/hmg/ddt439

    Article  PubMed  PubMed Central  Google Scholar 

  109. Nassisi M, Wohlschlegel J, Liu B et al (2020) Deep-phenotyping and further insights in ITM2B-related retinal dystrophy. Retina. https://doi.org/10.1097/IAE.0000000000002953

    Article  PubMed  Google Scholar 

  110. Giannoccaro MP, Bartoletti-Stella A, Piras S et al (2018) The first historically reported Italian family with FTD/ALS teaches a lesson on C9orf72 RE: clinical heterogeneity and Oligogenic inheritance. J Alzheimer’s Dis. https://doi.org/10.3233/JAD-170913

    Article  Google Scholar 

  111. Harris VK, Diamanduros A, Good P et al (2010) Bri2-23 is a potential cerebrospinal fluid biomarker in multiple sclerosis. Neurobiol Dis. https://doi.org/10.1016/j.nbd.2010.06.007

    Article  PubMed  PubMed Central  Google Scholar 

  112. Latil A, Chêne L, Mangin P et al (2003) Extensive analysis of the 13q14 region in human prostate tumors: DNA analysis and quantitative expression of genes lying in the interval of deletion. Prostate 57:39–50. https://doi.org/10.1002/pros.10272

    Article  CAS  PubMed  Google Scholar 

  113. Baron BW, Baron RM, Baron JM (2015) The ITM2B (BRI2) gene is a target of BCL6 repression: Implications for lymphomas and neurodegenerative diseases. Biochim Biophys Acta 1852:742–748. https://doi.org/10.1016/j.bbadis.2014.12.018

    Article  CAS  PubMed  Google Scholar 

  114. Lee S, Jeong J, Majewski T et al (2007) Forerunner genes contiguous to RB1 contribute to the development of in situ neoplasia. Proc Natl Acad Sci U S A. https://doi.org/10.1073/pnas.0701771104

    Article  PubMed  PubMed Central  Google Scholar 

  115. Creytens D, Van Gorp J, Savola S et al (2014) Atypical spindle cell lipoma: a clinicopathologic, immunohistochemical, and molecular study emphasizing its relationship to classical spindle cell lipoma. Virchows Arch. https://doi.org/10.1007/s00428-014-1568-8

    Article  PubMed  Google Scholar 

  116. Creytens D, Mentzel T, Ferdinande L et al (2017) Atypical pleomorphic lipomatous tumor: a clinicopathologic, immunohistochemical and molecular study of 21 cases, emphasizing its relationship to atypical spindle cell lipomatous tumor and suggesting a morphologic spectrum (Atypical spindle cell/Pleomorphi. Am J Surg Pathol. https://doi.org/10.1097/PAS.0000000000000936

Download references

Acknowledgements

This work was supported by the Instituto de Biomedicina‐iBiMED (UIDB/04501/2020 and POCI‐01‐0145‐FEDER‐007628); and the Fundação para a Ciência e Tecnologia (FCT) of the Ministério da Educação e Ciência, the COMPETE program, QREN and the EU (Fundo Europeu de Desenvolvimento Regional), Stiftelsen För Gamla Tjänarinnor, and Demensfonden from Demensförbundet. Authors acknowledge support from Integrated Programme of SR&TD “pAGE–Protein aggregation across lifespan” (CENTRO‐01‐0145‐FEDER‐000003), co‐funded by Centro 2020 Program, Portugal 2020, EU, through the European Regional Development Fund.

Author information

Author notes

  1. Simone Tambaro and Sandra Rebelo, these authors contributed equally to this work.

Authors and Affiliations

  1. Neuroscience and Signaling Laboratory, Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193, Aveiro, Portugal

    Filipa Martins, Isabela Santos, Odete A. B. da Cruz e Silva & Sandra Rebelo

  2. Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, 141 83, Huddinge, Sweden

    Simone Tambaro

Authors
  1. Filipa Martins
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Isabela Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Odete A. B. da Cruz e Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Simone Tambaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sandra Rebelo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Filipa Martins, Simone Tambaro or Sandra Rebelo.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martins, F., Santos, I., da Cruz e Silva, O.A.B. et al. The role of the integral type II transmembrane protein BRI2 in health and disease. Cell. Mol. Life Sci. 78, 6807–6822 (2021). https://doi.org/10.1007/s00018-021-03932-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-021-03932-5

Keywords

Search

Navigation