Top

Acta Neuropathologica Communications

Published in:

Open Access 01-12-2014 | Research

Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

Authors: Yoshinori Tanaka, James K Chambers, Takashi Matsuwaki, Keitaro Yamanouchi, Masugi Nishihara

Published in: Acta Neuropathologica Communications | Issue 1/2014

Abstract

Introduction

It has been shown that progranulin (PGRN) deficiency causes age-related neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Previous studies also suggested that PGRN is involved in modulating lysosomal function. To elucidate the pathophysiological role of PGRN in the aged brain, in the present study, lysosomal function and pathological changes of the brain were investigated using 10- and 90-week-old wild-type and PGRN-deficient mice.

Results

We showed that PGRN deficiency caused enhanced CD68 expression in activated microglia and astrogliosis in the cortex and thalamus, especially in the ventral posteromedial nucleus/ventral posterolateral nucleus (VPM/VPL), in the aged brain. Immunoreactivity for Lamp1 (lysosome marker) in the VPM/VPL and expression of lysosome-related genes, i.e. cathepsin D, V-type proton ATPase subunit d2, and transcription factor EB genes, were also increased by PGRN deficiency. Aggregates of p62, which is selectively degraded by the autophagy-lysosomal system, were observed in neuronal and glial cells in the VPM/VPL of aged PGRN-deficient mice. TAR DNA binding protein 43 (TDP-43) aggregates in the cytoplasm of neurons were also observed in aged PGRN-deficient mice. PGRN deficiency caused enhanced expression of glial cell-derived cytotoxic factors such as macrophage expressed gene 1, cytochrome b-245 light chain, cytochrome b-245 heavy chain, complement C4, tumor necrosis factor-α and lipocalin 2. In addition, neuronal loss and lipofuscinosis in the VPM/VPL and disrupted myelination in the cerebral cortex were observed in aged PGRN-deficient mice.

Conclusions

The present study shows that aged PGRN-deficient mice present with NCL-like pathology as well as TDP-43 aggregates in the VPM/VPL, where a particular vulnerability has been reported in NCL model mice. The present results also suggest that these pathological changes in the VPM/VPL are likely a result of lysosomal dysfunction. How PGRN prevents lysosomal dysfunction with aging remains to be elucidated.

Available only for authorised users

Cenik B, Sephton CF, Kutluk Cenik B, Herz J, Yu G: Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration. J Biol Chem 2012, 287: 32298–32306. 10.1074/jbc.R112.399170CrossRefPubMedPubMedCentral

Bateman A, Bennett HP: The granulin gene family: from cancer to dementia. Bioessays 2009, 31: 1245–1254. 10.1002/bies.200900086CrossRefPubMed

Thurner L, Preuss KD, Fadle N, Regitz E, Klemm P, Zaks M, Kemele M, Hasenfus A, Csernok E, Gross WL, Pasquali JL, Martin T, Bohle RM, Pfreundschuh M: Progranulin antibodies in autoimmune diseases. J Autoimmun 2013, 42: 29–38. 10.1016/j.jaut.2012.10.003CrossRefPubMed

Matsubara T, Mita A, Minami K, Hosooka T, Kitazawa S, Takahashi K, Tamori Y, Yokoi N, Watanabe M, Matsuo E, Nishimura O, Seino S: PGRN is a key adipokine mediating high fat diet-induced insulin resistanceand obesity through IL-6 in adipose tissue. Cell Metab 2012, 15: 38–50. 10.1016/j.cmet.2011.12.002CrossRefPubMed

Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M: Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006, 442: 916–919. 10.1038/nature05016CrossRefPubMed

Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den Broeck M, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C: Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006, 442: 920–924. 10.1038/nature05017CrossRefPubMed

Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T: TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 2006, 351: 602–611. 10.1016/j.bbrc.2006.10.093CrossRefPubMed

Tanaka Y, Matsuwaki T, Yamanouchi K, Nishihara M: Exacerbated inflammatory responses related to activated microglia after traumatic brain injury in progranulin-deficient mice. Neuroscience 2013, 231: 49–60. 10.1016/j.neuroscience.2012.11.032CrossRefPubMed

Tanaka Y, Matsuwaki T, Yamanouchi K, Nishihara M: Increased lysosomal biogenesis in activated microglia and exacerbated neuronal damage after traumatic brain injury in progranulin-deficient mice. Neuroscience 2013, 250: 8–19. 10.1016/j.neuroscience.2013.06.049CrossRefPubMed

10.

Conde JR, Streit WJ: Microglia in the aging brain. J Neuropathol Exp Neurol 2006, 65: 199–203. 10.1097/01.jnen.0000202887.22082.63CrossRefPubMed

11.

Wils H, Kleinberger G, Pereson S, Janssens J, Capell A, Van Dam D, Cuijt I, Joris G, De Deyn PP, Haass C, Van Broeckhoven C, Kumar-Singh S: Cellular ageing, increased mortality and FTLD-TDP-associated neuropathology in progranulin knockout mice. J Pathol 2012, 228: 67–76.PubMed

12.

Smith KR, Damiano J, Franceschetti S, Carpenter S, Canafoglia L, Morbin M, Rossi G, Pareyson D, Mole SE, Staropoli JF, Sims KB, Lewis J, Lin WL, Dickson DW, Dahl HH, Bahlo M, Berkovic SF: Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. Am J Hum Genet 2012, 90: 1102–1107. 10.1016/j.ajhg.2012.04.021CrossRefPubMedPubMedCentral

13.

Götzl JK, Damme M, Fellerer K, Tahirovic S, Kleinberger G, Janssens J, Van Der Zee J, Lang CM, Kremmer E, Martin JJ, Engelborghs S, Kretzschmar HA, Arzberger T, Van Broeckhoven C, Haass C, Capell A: Common pathobiochemical hallmarks of progranulin-associated frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis. Acta Neuropathol 2014. in press.

14.

Jalanko A, Braulke T: Neuronal ceroid lipofuscinoses. Biochim Biophys Acta 2009, 1793: 697–709. 10.1016/j.bbamcr.2008.11.004CrossRefPubMed

15.

Cooper JD: The neuronal ceroid lipofuscinoses: the same, but different? Biochem Soc Trans 2010, 38: 1448–1452. 10.1042/BST0381448CrossRefPubMed

16.

Kielar C, Maddox L, Bible E, Pontikis CC, Macauley SL, Griffey MA, Wong M, Sands MS, Cooper JD: Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis 2007, 25: 150–162. 10.1016/j.nbd.2006.09.001CrossRefPubMed

17.

Partanen S, Haapanen A, Kielar C, Pontikis C, Alexander N, Inkinen T, Saftig P, Gillingwater TH, Cooper JD, Tyynelä J: Synaptic changes in the thalamocortical system of cathepsin D-deficient mice: a model of human congenital neuronal ceroid-lipofuscinosis. J Neuropathol Exp Neurol 2008, 67: 16–29. 10.1097/nen.0b013e31815f3899CrossRefPubMed

18.

von Schantz C, Kielar C, Hansen SN, Pontikis CC, Alexander NA, Kopra O, Jalanko A, Cooper JD: Progressive thalamocortical neuron loss in Cln5 deficient mice: Distinct effects in Finnish variant late infantile NCL. Neurobiol Dis 2009, 34: 308–319. 10.1016/j.nbd.2009.02.001CrossRefPubMedPubMedCentral

19.

Blom T, Schmiedt ML, Wong AM, Kyttälä A, Soronen J, Jauhiainen M, Tyynelä J, Cooper JD, Jalanko A: Exacerbated neuronal ceroid lipofuscinosis phenotype in Cln1/5 double-knockout mice. Dis Model Mech 2013, 6: 342–357. 10.1242/dmm.010140CrossRefPubMed

20.

Kuronen M, Hermansson M, Manninen O, Zech I, Talvitie M, Laitinen T, Gröhn O, Somerharju P, Eckhardt M, Cooper JD, Lehesjoki AE, Lahtinen U, Kopra O: Galactolipid deficiency in the early pathogenesis of neuronal ceroid lipofuscinosis model Cln8 ^mnd: implications to delayed myelination and oligodendrocyte maturation. Neuropathol Appl Neurobiol 2012, 38: 471–486. 10.1111/j.1365-2990.2011.01233.xCrossRefPubMed

21.

Kayasuga Y, Chiba S, Suzuki M, Kikusui T, Matsuwaki T, Yamanouchi K, Kotaki H, Horai R, Iwakura Y, Nishihara M: Alteration of behavioural phenotype in mice by targeted disruption of the progranulin gene. Behav Brain Res 2007, 185: 110–118. 10.1016/j.bbr.2007.07.020CrossRefPubMed

22.

Oliveira VC, Carrara RC, Simoes DL, Saggioro FP, Carlotti CG Jr, Covas DT, Neder L: Sudan Black B treatment reduces autofluorescence and improves resolution of in situ hybridization specific fluorescent signals of brain sections. Histol Histopathol 2010, 25: 1017–1024.PubMed

23.

Sofroniew MV, Vinters HV: Astrocytes: biology and pathology. Acta Neuropathol 2010, 119: 7–35. 10.1007/s00401-009-0619-8CrossRefPubMed

24.

Boellaard JW, Schlote W, Hofer W: Species-specific ultrastructure of neuronal lipofuscin in hippocampus and neocortex of subhuman mammals and humans. Ultrastruct Pathol 2004, 28: 341–351. 10.1080/019131290882330CrossRefPubMed

25.

Boggs JM: Myelin basic protein: a multifunctional protein. Cell Mol Life Sci 2006, 63: 1945–1961. 10.1007/s00018-006-6094-7CrossRefPubMed

26.

Ferguson CJ, Lenk GM, Meisler MH: Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2. Hum Mol Genet 2009, 18: 4868–4878. 10.1093/hmg/ddp460CrossRefPubMedPubMedCentral

27.

Ju JS, Weihl CC: Inclusion body myopathy, Paget’s disease of the bone and fronto-temporal dementia: a disorder of autophagy. Hum Mol Genet 2010, 19: R38-R45. 10.1093/hmg/ddq157CrossRefPubMedPubMedCentral

28.

Yin F, Dumont M, Banerjee R, Ma Y, Li H, Lin MT, Beal MF, Nathan C, Thomas B, Ding A: Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia. FASEB J 2010, 24: 4639–4647. 10.1096/fj.10-161471CrossRefPubMedPubMedCentral

29.

Filimonenko M, Stuffers S, Raiborg C, Yamamoto A, Malerød L, Fisher EM, Isaacs A, Brech A, Stenmark H, Simonsen A: Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J Cell Biol 2007, 179: 485–500. 10.1083/jcb.200702115CrossRefPubMedPubMedCentral

30.

Wang X, Fan H, Ying Z, Li B, Wang H, Wang G: Degradation of TDP-43 and its pathogenic form by autophagy and the ubiquitin-proteasome system. Neurosci Lett 2010, 469: 112–116. 10.1016/j.neulet.2009.11.055CrossRefPubMed

31.

Caccamo A, Majumder S, Deng JJ, Bai Y, Thornton FB, Oddo S: Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability. J Biol Chem 2009, 284: 27416–27424. 10.1074/jbc.M109.031278CrossRefPubMedPubMedCentral

32.

Gomes C, Escrevente C, Costa J: Mutant superoxide dismutase 1 overexpression in NSC-34 cells: effect of trehalose on aggregation, TDP-43 localization and levels of co-expressed glycoproteins. Neurosci Lett 2010, 475: 145–149. 10.1016/j.neulet.2010.03.065CrossRefPubMed

33.

Ahmed Z, Sheng H, Xu YF, Lin WL, Innes AE, Gass J, Yu X, Wuertzer CA, Hou H, Chiba S, Yamanouchi K, Leissring M, Petrucelli L, Nishihara M, Hutton ML, McGowan E, Dickson DW, Lewis J: Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. Am J Pathol 2010, 177: 311–324. 10.2353/ajpath.2010.090915CrossRefPubMedPubMedCentral

34.

Kuronen M, Lehesjoki AE, Jalanko A, Cooper JD, Kopra O: Selective spatiotemporal patterns of glial activation and neuron loss in the sensory thalamocortical pathways of neuronal ceroid lipofuscinosis 8 mice. Neurobiol Dis 2012, 47: 444–457. 10.1016/j.nbd.2012.04.018CrossRefPubMed

35.

Kao AW, Eisenhut RJ, Martens LH, Nakamura A, Huang A, Bagley JA, Zhou P, de Luis A, Neukomm LJ, Cabello J, Farese RV Jr, Kenyon C: A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells. Proc Natl Acad Sci U S A 2011, 108: 4441–4446. 10.1073/pnas.1100650108CrossRefPubMedPubMedCentral

36.

Schulz K, Kroner A, David S: Iron efflux from astrocytes plays a role in remyelination. J Neurosci 2012, 32: 4841–4847. 10.1523/JNEUROSCI.5328-11.2012CrossRefPubMed

37.

Barateiro A, Domingues HS, Fernandes A, Relvas JB, Brites D: Rat cerebellar slice cultures exposed to bilirubin evidence reactive gliosis, excitotoxicity and impaired myelinogenesis that is prevented by AMPA and TNF-α inhibitors. Mol Neurobiol 2014, 49: 424–439. 10.1007/s12035-013-8530-7CrossRefPubMed

38.

Appelqvist H, Wäster P, Kågedal K, Ollinger K: The lysosome: from waste bag to potential therapeutic target. J Mol Cell Biol 2013, 5: 214–226. 10.1093/jmcb/mjt022CrossRefPubMed

39.

Brady OA, Zheng Y, Murphy K, Huang M, Hu F: The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Hum Mol Genet 2013, 22: 685–695. 10.1093/hmg/dds475CrossRefPubMed

Title: Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice
Authors: Yoshinori Tanaka
James K Chambers
Takashi Matsuwaki
Keitaro Yamanouchi
Masugi Nishihara
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2014
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-014-0078-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

Abstract

Introduction

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2014

Neuronal injury biomarkers and prognosis in ADNI subjects with normal cognition

The prion protein protease sensitivity, stability and seeding activity in variably protease sensitive prionopathy brain tissue suggests molecular overlaps with sporadic Creutzfeldt-Jakob disease

Sporadic hemangioblastomas are characterized by cryptic VHL inactivation

Reducing hippocampal extracellular matrix reverses early memory deficits in a mouse model of Alzheimer’s disease

Abundant kif21b is associated with accelerated progression in neurodegenerative diseases

The identification of mitochondrial DNA variants in glioblastoma multiforme