Lysosomal Dysfunction Promotes Cleavage and Neurotoxicity of Tau

English version České info

Expansion of the lysosomal system, including cathepsin D upregulation, is an early and prominent finding in Alzheimer's disease brain. Cell culture studies, however, have provided differing perspectives on the lysosomal connection to Alzheimer's disease, including both protective and detrimental influences. We sought to clarify and molecularly define the connection in vivo in a genetically tractable model organism. Cathepsin D is upregulated with age in a Drosophila model of Alzheimer's disease and related tauopathies. Genetic analysis reveals that cathepsin D plays a neuroprotective role because genetic ablation of cathepsin D markedly potentiates tau-induced neurotoxicity. Further, generation of a C-terminally truncated form of tau found in Alzheimer's disease patients is significantly increased in the absence of cathepsin D. We show that truncated tau has markedly increased neurotoxicity, while solubility of truncated tau is decreased. Importantly, the toxicity of truncated tau is not affected by removal of cathepsin D, providing genetic evidence that modulation of neurotoxicity by cathepsin D is mediated through C-terminal cleavage of tau. We demonstrate that removing cathepsin D in adult postmitotic neurons leads to aberrant lysosomal expansion and caspase activation in vivo, suggesting a mechanism for C-terminal truncation of tau. We also demonstrate that both cathepsin D knockout mice and cathepsin D–deficient sheep show abnormal C-terminal truncation of tau and accompanying caspase activation. Thus, caspase cleavage of tau may be a molecular mechanism through which lysosomal dysfunction and neurodegeneration are causally linked in Alzheimer's disease.

Vyšlo v časopise: Lysosomal Dysfunction Promotes Cleavage and Neurotoxicity of Tau. PLoS Genet 6(7): e32767. doi:10.1371/journal.pgen.1001026
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001026

Souhrn

Zdroje

1. FutermanAH

van MeerG

2004 The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol 5 554 565

2. CataldoAM

BarnettJL

BermanSA

LiJ

QuarlessS

1995 Gene expression and cellular content of cathepsin D in Alzheimer's disease brain: evidence for early up-regulation of the endosomal-lysosomal system. Neuron 14 671 680

3. NixonRA

CataldoAM

2006 Lysosomal system pathways: genes to neurodegeneration in Alzheimer's disease. J Alzheimers Dis 9 277 289

4. LimF

HernándezF

LucasJJ

Gómez-RamosP

MoránMA

2001 FTDP-17 mutations in tau transgenic mice provoke lysosomal abnormalities and Tau filaments in forebrain. Mol Cell Neurosci 18 702 714

5. WangY

Martinez-VicenteM

KrügerU

KaushikS

WongE

2009 Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet 18 4153 4170

6. ZhangL

ShengR

QinZ

2009 The lysosome and neurodegenerative diseases. Acta Biochim Biophys Sin (Shanghai) 41 437 445

7. BoyaP

KroemerG

2008 Lysosomal membrane permeabilization in cell death. Oncogene 27 6434 6451

8. BendiskeJ

BahrBA

2003 Lysosomal activation is a compensatory response against protein accumulation and associated synaptopathogenesis–an approach for slowing Alzheimer disease? J Neuropathol Exp Neurol 62 451 463

9. CallahanLM

VaulesWA

ColemanPD

1999 Quantitative decrease in synaptophysin message expression and increase in cathepsin D message expression in Alzheimer disease neurons containing neurofibrillary tangles. J Neuropathol Exp Neurol 58 275 287

10. CataldoAM

HamiltonDJ

BarnettJL

PaskevichPA

NixonRA

1996 Properties of the endosomal-lysosomal system in the human central nervous system: disturbances mark most neurons in populations at risk to degenerate in Alzheimer's disease. J Neurosci 16 186 199

11. BeyerK

LaoJI

LatorreP

ArizaA

2005 Age at onset: an essential variable for the definition of genetic risk factors for sporadic Alzheimer's disease. Ann N Y Acad Sci 1057 260 278

12. PapassotiropoulosA

BagliM

KurzA

KornhuberJ

FörstlH

2000 A genetic variation of cathepsin D is a major risk factor for Alzheimer's disease. Ann Neurol 47 399 403

13. SiintolaE

PartanenS

StrommeP

HaapanenA

HaltiaM

2006 Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain 129 1438 1445

14. SteinfeldR

ReinhardtK

SchreiberK

HillebrandM

KraetznerR

2006 Cathepsin D deficiency is associated with a human neurodegenerative disorder. Am J Hum Genet 78 988 998

15. YamashimaT

OikawaS

2009 The role of lysosomal rupture in neuronal death. Progress in Neurobiology 1 16

16. BiX

ZhouJ

LynchG

1999 Lysosomal protease inhibitors induce meganeurites and tangle-like structures in entorhinohippocampal regions vulnerable to Alzheimer's disease. Exp Neurol 158 312 327

17. Dias-SantagataD

FulgaTA

DuttaroyA

FeanyMB

2007 Oxidative stress mediates tau-induced neurodegeneration in Drosophila. J Clin Invest 117 236 245

18. KhuranaV

LuY

SteinhilbML

OldhamS

ShulmanJM

2006 TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr Biol 16 230 241

19. WittmannCW

WszolekMF

ShulmanJM

SalvaterraPM

LewisJ

2001 Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293 711 714

20. FulgaTA

Elson-SchwabI

KhuranaV

SteinhilbML

SpiresTL

2007 Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat Cell Biol 9 139 148

21. ScherzerCR

JensenRV

GullansSR

FeanyMB

2003 Gene expression changes presage neurodegeneration in a Drosophila model of Parkinson's disease. Hum Mol Genet 12 2457 2466

22. MyllykangasL

TyynelaJ

Page-McCawA

RubinGM

HaltiaMJ

2005 Cathepsin D-deficient Drosophila recapitulate the key features of neuronal ceroid lipofuscinoses. Neurobiol Dis 19 194 199

23. AndorferC

AckerCM

KressY

HofPR

DuffK

2005 Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci 25 5446 5454

24. JaworskiT

DewachterI

LechatB

CroesS

TermontA

2009 AAV-tau mediates pyramidal neurodegeneration by cell-cycle re-entry without neurofibrillary tangle formation in wild-type mice. PLoS One 4 e7280 doi:10.1371/journal.pone.0007280

25. GhoshS

FeanyMB

2004 Comparison of pathways controlling toxicity in the eye and brain in Drosophila models of human neurodegenerative diseases. Hum Mol Genet 13 2011 2018

26. WarrickJM

PaulsonHL

Gray-BoardGL

BuiQT

FischbeckKH

1998 Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 93 939 949

27. JacksonGR

Wiedau-PazosM

SangTK

WagleN

BrownCA

2002 Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 34 509 519

28. NishimuraI

YangY

LuB

2004 PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila. Cell 116 671 682

29. SteinhilbML

Dias-SantagataD

FulgaTA

FelchDL

FeanyMB

2007 Tau phosphorylation sites work in concert to promote neurotoxicity in vivo. Mol Biol Cell 18 5060 5068

30. BednarskiE

LynchG

1998 Selective suppression of cathepsin L results from elevations in lysosomal pH and is followed by proteolysis of tau protein. Neuroreport 9 2089 2094

31. GamblinTC

ChenF

ZambranoA

AbrahaA

LagalwarS

2003 Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc Natl Acad Sci USA 100 10032 10037

32. Guillozet-BongaartsAL

Garcia-SierraF

ReynoldsMR

HorowitzPM

FuY

2005 Tau truncation during neurofibrillary tangle evolution in Alzheimer's disease. Neurobiol Aging 26 1015 1022

33. RissmanRA

PoonWW

Blurton-JonesM

OddoS

TorpR

2004 Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest 114 121 130

34. ChungCW

SongYH

KimIK

YoonWJ

RyuBR

2001 Proapoptotic effects of tau cleavage product generated by caspase-3. Neurobiol Dis 8 162 172

35. FasuloL

UgoliniG

CattaneoA

2005 Apoptotic effect of caspase-3 cleaved tau in hippocampal neurons and its potentiation by tau FTDP-mutation N279K. J Alzheimers Dis 7 3 13

36. Matthews-RobersonTA

QuintanillaRA

DingH

JohnsonGV

2008 Immortalized cortical neurons expressing caspase-cleaved tau are sensitized to endoplasmic reticulum stress induced cell death. Brain Res 1234 206 212

37. BrenneckeJ

HipfnerDR

StarkA

RussellRB

CohenSM

2003 bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113 25 36

38. CullenK

McCallK

2004 Role of programmed cell death in patterning the Drosophila antennal arista. Developmental Biology 275 82 92

39. AbrahaA

GhoshalN

GamblinTC

CrynsV

BerryRW

2000 C-terminal inhibition of tau assembly in vitro and in Alzheimer's disease. J Cell Sci 113 Pt 21 3737 3745

40. YinH

KuretJ

2006 C-terminal truncation modulates both nucleation and extension phases of tau fibrillization. FEBS Lett 580 211 215

41. WilliamsDW

KondoS

KrzyzanowskaA

HiromiY

TrumanJW

2006 Local caspase activity directs engulfment of dendrites during pruning. Nat Neurosci 9 1234 1236

42. MutkaAL

HaapanenA

KakelaR

LindforsM

WrightAK

2009 Murine cathepsin D deficiency is associated with dysmyelination/myelin disruption and accumulation of cholesteryl esters in the brain. J Neurochem

43. TyyneläJ

SoharI

SleatDE

GinRM

DonnellyRJ

2000 A mutation in the ovine cathepsin D gene causes a congenital lysosomal storage disease with profound neurodegeneration. Embo J 19 2786 2792

44. CataldoAM

NixonRA

1990 Enzymatically active lysosomal proteases are associated with amyloid deposits in Alzheimer brain. Proc Natl Acad Sci USA 87 3861 3865

45. HaltiaM

2003 The neuronal ceroid-lipofuscinoses. J Neuropathol Exp Neurol 62 1 13

46. JeyakumarM

DwekRA

ButtersTD

PlattFM

2005 Storage solutions: treating lysosomal disorders of the brain. Nat Rev Neurosci 6 713 725

47. CastanoEM

RoherAE

EshCL

KokjohnTA

BeachT

2006 Comparative proteomics of cerebrospinal fluid in neuropathologically-confirmed Alzheimer's disease and non-demented elderly subjects. Neurol Res 28 155 163

48. UrbanelliL

EmilianiC

MassiniC

PersichettiE

OrlacchioA

2008 Cathepsin D expression is decreased in Alzheimer's disease fibroblasts. Neurobiol Aging 29 12 22

49. HaroldD

AbrahamR

HollingworthP

SimsR

GerrishA

Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet 41(10) 1088 1093

50. LambertJC

HeathS

EvenG

CampionD

SleegersK

2009 Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet 41 1094 1099

51. SchuurM

IkramMA

van SwietenJC

IsaacsA

Vergeer-DropJM

2009 Cathepsin D gene and the risk of Alzheimer's disease: A population-based study and meta-analysis. Neurobiol Aging

52. JalankoA

BraulkeT

2009 Neuronal ceroid lipofuscinoses. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1793 697 709

53. Spires-JonesTL

StoothoffWH

de CalignonA

JonesPB

HymanBT

2009 Tau pathophysiology in neurodegeneration: a tangled issue. Trends Neurosci 32 150 159

54. LeeVM

GoedertM

TrojanowskiJQ

2001 Neurodegenerative tauopathies. Annu Rev Neurosci 24 1121 1159

55. HardyJ

SelkoeDJ

2002 The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297 353 356

56. HuttonM

LendonCL

RizzuP

BakerM

FroelichS

1998 Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393 702 705

57. PoorkajP

BirdTD

WijsmanE

NemensE

GarrutoRM

1998 Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 43 815 825

58. SpillantiniMG

MurrellJR

GoedertM

FarlowMR

KlugA

1998 Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A 95 7737 7741

59. GotzJ

ChenF

van DorpeJ

NitschRM

2001 Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293 1491 1495

60. LewisJ

DicksonDW

LinWL

ChisholmL

CorralA

2001 Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293 1487 1491

61. RobersonED

Scearce-LevieK

PalopJJ

YanF

ChengIH

2007 Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science 316 750 754

62. NewmanJ

RissmanRA

SarsozaF

KimRC

DickM

2005 Caspase-cleaved tau accumulation in neurodegenerative diseases associated with tau and alpha-synuclein pathology. Acta Neuropathol 110 135 144

63. LiuCL

ChenS

DietrichD

HuBR

2008 Changes in autophagy after traumatic brain injury. J Cereb Blood Flow Metab 28 674 683

64. WangY

Martinez-VicenteM

KrügerU

KaushikS

WongE

2009 Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet 18 4153 4170

65. MorinX

DanemanR

ZavortinkM

ChiaW

2001 A protein trap strategy to detect GFP-tagged proteins expressed from their endogenous loci in Drosophila. Proc. Natl. Acad. Sci USA 98 15050 15055

66. LeeMK

StirlingW

XuY

XuX

QuiD

2002 Human alpha-synuclein-harboring familial Parkinson's disease-linked Ala-53→Thr mutation causes neurodegenerative disease with alpha- synuclein aggregation in transgenic mice. Proc Natl Acad Sci U S A 99 8968 8973