Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2012

Open Access 01-12-2012 | Research article

Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway

Authors: Keiichi Inoue, Joanne Rispoli, Hanoch Kaphzan, Eric Klann, Emily I Chen, Jongpil Kim, Masaaki Komatsu, Asa Abeliovich

Published in: Molecular Neurodegeneration | Issue 1/2012

Login to get access

Abstract

Background

Macroautophagy is an evolutionarily conserved mechanism for bulk intracellular degradation of proteins and organelles. Pathological studies have implicated macroautophagy defects in human neurodegenerative disorders of aging including Alzheimer’s disease and tauopathies. Neuronal deficiency of macroautophagy throughout mouse embryonic development results in neurodevelopmental defects and early postnatal mortality. However, the role of macroautophagy in mature CNS neurons, and the relationship with human disease neuropathology, remains unclear. Here we describe mice deficient in an essential macroautophagy component, Atg7, specifically within postnatal CNS neurons.

Results

Postnatal forebrain-specific Atg7 conditional knockout (cKO) mice displayed age-dependent neurodegeneration and ubiquitin- and p62-positive inclusions. Phosphorylated tau was significantly accumulated in Atg7 cKO brains, but neurofibrillary tangles that typify end-stage human tauopathy were not apparent. A major tau kinase, glycogen synthase kinase 3β (GSK3β), was also accumulated in Atg7 cKO brains. Chronic pharmacological inhibition of tau phosphorylation, or genetic deletion of tau, significantly rescued Atg7-deficiency-mediated neurodegeneration, but did not suppress inclusion formation.

Conclusions

These data elucidate a role for macroautophagy in the long-term survival and physiological function of adult CNS neurons. Neurodegeneration in the context of macroautophagy deficiency is mediated through a phospho-tau pathway.
Appendix
Available only for authorised users
Literature
1.
Abeliovich A, Flint Beal M: Parkinsonism genes: culprits and clues. J Neurochem. 2006, 99: 1062-1072. 10.1111/j.1471-4159.2006.04102.x.CrossRefPubMed
2.
Ross CA, Poirier MA: Protein aggregation and neurodegenerative disease. Nat Med. 2004, 10 (Suppl): S10-S17.CrossRefPubMed
3.
Selkoe DJ: Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseases. Nat Cell Biol. 2004, 6: 1054-1061. 10.1038/ncb1104-1054.CrossRefPubMed
4.
Petrucelli L, Dawson TM: Mechanism of neurodegenerative disease: role of the ubiquitin proteasome system. Ann Med. 2004, 36: 315-320. 10.1080/07853890410031948.CrossRefPubMed
5.
Nixon RA: Autophagy in neurodegenerative disease: friend, foe or turncoat?. Trends Neurosci. 2006, 29: 528-535. 10.1016/j.tins.2006.07.003.CrossRefPubMed
6.
Anglade P, Vyas S, Javoy-Agid F, Herrero MT, Michel PP, Marquez J, Mouatt-Prigent A, Ruberg M, Hirsch EC, Agid Y: Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease. Histol Histopathol. 1997, 12: 25-31.PubMed
7.
8.
Klionsky DJ, Ohsumi Y: Vacuolar import of proteins and organelles from the cytoplasm. Annu Rev Cell Dev Biol. 1999, 15: 1-32. 10.1146/annurev.cellbio.15.1.1.CrossRefPubMed
9.
Cuervo AM, Wong ES, Martinez-Vicente M: Protein degradation, aggregation, and misfolding. Mov Disord. 2010, 25 (Suppl 1): S49-S54.CrossRefPubMed
10.
Boland B, Kumar A, Lee S, Platt FM, Wegiel J, Yu WH, Nixon RA: Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease. J Neurosci. 2008, 28: 6926-6937. 10.1523/JNEUROSCI.0800-08.2008.PubMedCentralCrossRefPubMed
11.
Eblan MJ, Walker JM, Sidransky E: The glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med. 2005, 352: 728-731. author reply 728-731CrossRefPubMed
12.
Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D, Cid LP, Goebel I, Mubaidin AF, Wriekat AL, Roeper J, et al: Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet. 2006, 38: 1184-1191. 10.1038/ng1884.CrossRefPubMed
13.
Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K: Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006, 441: 880-884. 10.1038/nature04723.CrossRefPubMed
14.
Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N: Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006, 441: 885-889. 10.1038/nature04724.CrossRefPubMed
15.
Nishiyama J, Miura E, Mizushima N, Watanabe M, Yuzaki M: Aberrant membranes and double-membrane structures accumulate in the axons of Atg5-null Purkinje cells before neuronal death. Autophagy. 2007, 3: 591-596.CrossRefPubMed
16.
17.
Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, Mizushima N, Iwata J, Ezaki J, Murata S, et al: Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell. 2007, 131: 1149-1163. 10.1016/j.cell.2007.10.035.CrossRefPubMed
18.
Klionsky DJ: Neurodegeneration: good riddance to bad rubbish. Nature. 2006, 441: 819-820. 10.1038/441819a.CrossRefPubMed
19.
Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y, Uchiyama Y, et al: Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol. 2005, 169: 425-434. 10.1083/jcb.200412022.PubMedCentralCrossRefPubMed
20.
Tsien JZ, Chen DF, Gerber D, Tom C, Mercer EH, Anderson DJ, Mayford M, Kandel ER, Tonegawa S: Subregion- and cell type-restricted gene knockout in mouse brain. Cell. 1996, 87: 1317-1326. 10.1016/S0092-8674(00)81826-7.CrossRefPubMed
21.
Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Overvatn A, Bjorkoy G, Johansen T: p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 2007, 282: 24131-24145. 10.1074/jbc.M702824200.CrossRefPubMed
22.
Yu WH, Kumar A, Peterhoff C, Shapiro Kulnane L, Uchiyama Y, Lamb BT, Cuervo AM, Nixon RA: Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for beta-amyloid peptide over-production and localization in Alzheimer's disease. Int J Biochem Cell Biol. 2004, 36: 2531-2540. 10.1016/j.biocel.2004.05.010.CrossRefPubMed
23.
Wang Y, Martinez-Vicente M, Kruger U, Kaushik S, Wong E, Mandelkow EM, Cuervo AM, Mandelkow E: Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet. 2009, 18: 4153-4170. 10.1093/hmg/ddp367.PubMedCentralCrossRefPubMed
24.
Hamano T, Gendron TF, Causevic E, Yen SH, Lin WL, Isidoro C, Deture M, Ko LW: Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression. Eur J Neurosci. 2008, 27: 1119-1130. 10.1111/j.1460-9568.2008.06084.x.CrossRefPubMed
25.
Sarkar S, Rubinsztein DC: Huntington's disease: degradation of mutant huntingtin by autophagy. FEBS J. 2008, 275: 4263-4270. 10.1111/j.1742-4658.2008.06562.x.CrossRefPubMed
26.
Qin ZH, Wang Y, Kegel KB, Kazantsev A, Apostol BL, Thompson LM, Yoder J, Aronin N, DiFiglia M: Autophagy regulates the processing of amino terminal huntingtin fragments. Hum Mol Genet. 2003, 12: 3231-3244. 10.1093/hmg/ddg346.CrossRefPubMed
27.
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.2009.11.055.CrossRefPubMed
28.
Urushitani M, Sato T, Bamba H, Hisa Y, Tooyama I: Synergistic effect between proteasome and autophagosome in the clearance of polyubiquitinated TDP-43. J Neurosci Res. 2010, 88: 784-797.PubMed
29.
Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC: Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem. 2003, 278: 25009-25013. 10.1074/jbc.M300227200.CrossRefPubMed
30.
Zhou L, Miller BL, McDaniel CH, Kelly L, Kim OJ, Miller CA: Frontotemporal dementia: neuropil spheroids and presynaptic terminal degeneration. Ann Neurol. 1998, 44: 99-109. 10.1002/ana.410440116.CrossRefPubMed
31.
Dickson DW: Neuropathology of Pick's disease. Neurology. 2001, 56: S16-S20. 10.1212/WNL.56.suppl_4.S16.CrossRefPubMed
32.
Luna-Munoz J, Chavez-Macias L, Garcia-Sierra F, Mena R: Earliest stages of tau conformational changes are related to the appearance of a sequence of specific phospho-dependent tau epitopes in Alzheimer's disease. J Alzheimers Dis. 2007, 12: 365-375.PubMed
33.
Mazanetz MP, Fischer PM: Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases. Nat Rev Drug Discov. 2007, 6: 464-479. 10.1038/nrd2111.CrossRefPubMed
34.
Yoshimura T, Kawano Y, Arimura N, Kawabata S, Kikuchi A, Kaibuchi K: GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell. 2005, 120: 137-149. 10.1016/j.cell.2004.11.012.CrossRefPubMed
35.
Selenica ML, Jensen HS, Larsen AK, Pedersen ML, Helboe L, Leist M, Lotharius J: Efficacy of small-molecule glycogen synthase kinase-3 inhibitors in the postnatal rat model of tau hyperphosphorylation. Br J Pharmacol. 2007, 152: 959-979. 10.1038/sj.bjp.0707471.PubMedCentralCrossRefPubMed
36.
Leost M, Schultz C, Link A, Wu YZ, Biernat J, Mandelkow EM, Bibb JA, Snyder GL, Greengard P, Zaharevitz DW, et al: Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25. Eur J Biochem. 2000, 267: 5983-5994. 10.1046/j.1432-1327.2000.01673.x.CrossRefPubMed
37.
Dawson HN, Ferreira A, Eyster MV, Ghoshal N, Binder LI, Vitek MP: Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J Cell Sci. 2001, 114: 1179-1187.PubMed
38.
Jimenez-Mateos EM, Gonzalez-Billault C, Dawson HN, Vitek MP, Avila J: Role of MAP1B in axonal retrograde transport of mitochondria. Biochem J. 2006, 397: 53-59. 10.1042/BJ20060205.PubMedCentralCrossRefPubMed
39.
Ishizawa T, Sahara N, Ishiguro K, Kersh J, McGowan E, Lewis J, Hutton M, Dickson DW, Yen SH: Co-localization of glycogen synthase kinase-3 with neurofibrillary tangles and granulovacuolar degeneration in transgenic mice. Am J Pathol. 2003, 163: 1057-1067. 10.1016/S0002-9440(10)63465-7.PubMedCentralCrossRefPubMed
40.
Ferrer I, Barrachina M, Tolnay M, Rey MJ, Vidal N, Carmona M, Blanco R, Puig B: Phosphorylated protein kinases associated with neuronal and glial tau deposits in argyrophilic grain disease. Brain Pathol. 2003, 13: 62-78.CrossRefPubMed
41.
Ferrer I, Barrachina M, Puig B: Glycogen synthase kinase-3 is associated with neuronal and glial hyperphosphorylated tau deposits in Alzheimer's disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration. Acta Neuropathol. 2002, 104: 583-591.PubMed
42.
Leroy K, Yilmaz Z, Brion JP: Increased level of active GSK-3beta in Alzheimer's disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration. Neuropathol Appl Neurobiol. 2007, 33: 43-55.PubMed
43.
Leroy K, Boutajangout A, Authelet M, Woodgett JR, Anderton BH, Brion JP: The active form of glycogen synthase kinase-3beta is associated with granulovacuolar degeneration in neurons in Alzheimer's disease. Acta Neuropathol. 2002, 103: 91-99. 10.1007/s004010100435.CrossRefPubMed
44.
Brunden KR, Trojanowski JQ, Lee VM: Evidence that non-fibrillar tau causes pathology linked to neurodegeneration and behavioral impairments. J Alzheimers Dis. 2008, 14: 393-399.PubMedCentralPubMed
45.
Hoozemans JJ, van Haastert ES, Nijholt DA, Rozemuller AJ, Eikelenboom P, Scheper W: The unfolded protein response is activated in pretangle neurons in Alzheimer's disease hippocampus. Am J Pathol. 2009, 174: 1241-1251. 10.2353/ajpath.2009.080814.PubMedCentralCrossRefPubMed
46.
Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM: Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol. 2005, 64: 113-122.PubMed
47.
Sasaki S: Autophagy in spinal cord motor neurons in sporadic amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 2011, 70: 349-359. 10.1097/NEN.0b013e3182160690.CrossRefPubMed
48.
Sun Y, Liou B, Ran H, Skelton MR, Williams MT, Vorhees CV, Kitatani K, Hannun YA, Witte DP, Xu YH, Grabowski GA: Neuronopathic Gaucher disease in the mouse: viable combined selective saposin C deficiency and mutant glucocerebrosidase (V394L) mice with glucosylsphingosine and glucosylceramide accumulation and progressive neurological deficits. Hum Mol Genet. 2010, 19: 1088-1097. 10.1093/hmg/ddp580.PubMedCentralCrossRefPubMed
49.
Nagata E, Sawa A, Ross CA, Snyder SH: Autophagosome-like vacuole formation in Huntington's disease lymphoblasts. Neuroreport. 2004, 15: 1325-1328. 10.1097/01.wnr.0000127073.66692.8f.CrossRefPubMed
50.
Nixon RA, Yang DS, Lee JH: Neurodegenerative lysosomal disorders: a continuum from development to late age. Autophagy. 2008, 4: 590-599.CrossRefPubMed
51.
Komatsu M, Wang QJ, Holstein GR, Friedrich VL, Iwata J, Kominami E, Chait BT, Tanaka K, Yue Z: Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc Natl Acad Sci U S A. 2007, 104: 14489-14494. 10.1073/pnas.0701311104.PubMedCentralCrossRefPubMed
52.
Friedman LG, Lachenmayer ML, Wang J, He L, Poulose SM, Komatsu M, Holstein GR, Yue Z: Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of alpha-synuclein and LRRK2 in the brain. J Neurosci. 2012, 32: 7585-7593. 10.1523/JNEUROSCI.5809-11.2012.PubMedCentralCrossRefPubMed
53.
Taelman VF, Dobrowolski R, Plouhinec JL, Fuentealba LC, Vorwald PP, Gumper I, Sabatini DD, De Robertis EM: Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes. Cell. 2010, 143: 1136-1148. 10.1016/j.cell.2010.11.034.PubMedCentralCrossRefPubMed
54.
Mizushima N, Levine B, Cuervo AM, Klionsky DJ: Autophagy fights disease through cellular self-digestion. Nature. 2008, 451: 1069-1075. 10.1038/nature06639.PubMedCentralCrossRefPubMed
55.
Lin SY, Li TY, Liu Q, Zhang C, Li X, Chen Y, Zhang SM, Lian G, Ruan K, Wang Z, et al: GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. Science. 2012, 336: 477-481. 10.1126/science.1217032.CrossRefPubMed
56.
Sarkar S, Krishna G, Imarisio S, Saiki S, O'Kane CJ, Rubinsztein DC: A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin. Hum Mol Genet. 2008, 17: 170-178.CrossRefPubMed
57.
Lin WL, Lewis J, Yen SH, Hutton M, Dickson DW: Ultrastructural neuronal pathology in transgenic mice expressing mutant (P301L) human tau. J Neurocytol. 2003, 32: 1091-1105.CrossRefPubMed
58.
Pacheco CD, Elrick MJ, Lieberman AP: Tau deletion exacerbates the phenotype of Niemann-Pick type C mice and implicates autophagy in pathogenesis. Hum Mol Genet. 2009, 18: 956-965.PubMedCentralPubMed
59.
60.
Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L: High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci. 2000, 20: 4050-4058.PubMed
61.
Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y: In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell. 2004, 15: 1101-1111.PubMedCentralCrossRefPubMed
62.
Zhuang X, Masson J, Gingrich JA, Rayport S, Hen R: Targeted gene expression in dopamine and serotonin neurons of the mouse brain. J Neurosci Methods. 2005, 143: 27-32. 10.1016/j.jneumeth.2004.09.020.CrossRefPubMed
Metadata
Title
Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway
Authors
Keiichi Inoue
Joanne Rispoli
Hanoch Kaphzan
Eric Klann
Emily I Chen
Jongpil Kim
Masaaki Komatsu
Asa Abeliovich
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2012
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/1750-1326-7-48

Other articles of this Issue 1/2012

Molecular Neurodegeneration 1/2012 Go to the issue

Research article

The I2020T Leucine-rich repeat kinase 2 transgenic mouse exhibits impaired locomotive ability accompanied by dopaminergic neuron abnormalities

Research article

Exosomal cell-to-cell transmission of alpha synuclein oligomers

Research article

Motor neuron apoptosis and neuromuscular junction perturbation are prominent features in a Drosophila model of Fus-mediated ALS

Research article

Regulation of mitochondrial permeability transition pore by PINK1

Research article

Frataxin deficiency unveils cell-context dependent actions of insulin-like growth factor I on neurons

Research article

Quantitative connection between polyglutamine aggregation kinetics and neurodegenerative process in patients with Huntington’s disease