Endosomal accumulation of APP in wobbler motor neurons reflects impaired vesicle trafficking: Implications for human motor neuron disease
Tóm tắt
The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown but hypotheses about disease mechanisms include oxidative stress, defective axonal transport, mitochondrial dysfunction and disrupted RNA processing. Whereas familial ALS is well represented by transgenic mutant SOD1 mouse models, the mouse mutant wobbler (WR) develops progressive motor neuron degeneration due to a point mutation in the Vps54 gene, and provides an animal model for sporadic ALS. VPS54 protein as a component of a protein complex is involved in vesicular Golgi trafficking; impaired vesicle trafficking might also be mechanistic in the pathogenesis of human ALS. In motor neurons of homozygous symptomatic WR mice, a massive number of endosomal vesicles significantly enlarged (up to 3 μm in diameter) were subjected to ultrastructural analysis and immunohistochemistry for the endosome-specific small GTPase protein Rab7 and for amyloid precursor protein (APP). Enlarged vesicles were neither detected in heterozygous WR nor in transgenic SOD1(G93A) mice; in WR motor neurons, numerous APP/Rab7-positive vesicles were observed which were mostly LC3-negative, suggesting they are not autophagosomes. We conclude that endosomal APP/Rab7 staining reflects impaired vesicle trafficking in WR mouse motor neurons. Based on these findings human ALS tissues were analysed for APP in enlarged vesicles and were detected in spinal cord motor neurons in six out of fourteen sporadic ALS cases. These enlarged vesicles were not detected in any of the familial ALS cases. Thus our study provides the first evidence for wobbler-like aetiologies in human ALS and suggests that the genes encoding proteins involved in vesicle trafficking should be screened for pathogenic mutations.
Tài liệu tham khảo
Yankner BA, Lu T: Amyloid beta -protein toxicity and the pathogenesis of Alzheimer's disease. J Biol Chem. 2009, 284: 4755-4759. 10.1074/jbc.R800018200.
Jin LW, Shie FS, Maezawa I, Vincent I, Bird T: Intracellular accumulation of amyloidogenic fragments of amyloid-beta precursor protein in neurons with Niemann-Pick type C defects is associated with endosomal abnormalities. Am J Pathol. 2004, 164: 975-985. 10.1016/S0002-9440(10)63185-9.
Koistinen H, Prinjha R, Soden P, Harper A, Banner SJ, Pradat PF, Loeffler JP, Dingwall C: Elevated levels of amyloid precursor protein in muscle of patients with amyotrophic lateral sclerosis and a mouse model of the disease. Muscle Nerve. 2006, 34: 444-450. 10.1002/mus.20612.
Falconer DS: Wobbler (wr). Mouse News Letters. 1956, 15: 22.
Kaupmann K, Simon-Chazottes D, Guenet JL, Jockusch H: Wobbler, a mutation affecting motoneuron survival and gonadal functions in the mouse, maps to proximal chromosome 11. Genomics. 1992, 13: 39-43. 10.1016/0888-7543(92)90199-3.
Schmitt-John T, Drepper C, Mussmann A, Hahn P, Kuhlmann M, Thiel C, Hafner M, Lengeling A, Heimann P, Jones JM, Meisler MH, Jockusch H: Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse. Nat Genet. 2005, 37: 1213-1215. 10.1038/ng1661.
Conibear E, Stevens TH: Vps52p, Vps53p, and Vps54p form a novel multisubunit complex required for protein sorting at the yeast late Golgi. Mol Biol Cell. 2000, 11: 305-323.
Liewen H, Meinhold-Heerlein I, Oliveira V, Schwarzenbacher R, Luo G, Wadle A, Jung M, Pfreundschuh M, Stenner-Liewen F: Characterization of the human GARP (Golgi associated retrograde protein) complex. Exp Cell Res. 2005, 306: 24-34. 10.1016/j.yexcr.2005.01.022.
Pérez-Victoria FJ, Abascal-Palacios G, Tascón I, Kajava A, Magadán JG, Pioro EP, Bonifacino JS, Hierro A: Structural basis for the wobbler mouse neurodegenerative disorder caused by mutation in the Vps54 subunit of the GARP complex. Proc Natl Acad Sci USA. 2010, 107: 12860-12865.
Rathke-Hartlieb S, Schmidt VC, Jockusch H, Schmitt-John T, Bartsch JW: Spatiotemporal progression of neurodegeneration and glia activation in the wobbler neuropathy of the mouse. Neuroreport. 1999, 10: 3411-3416. 10.1097/00001756-199911080-00028.
Mitsumoto H, Bradley WG: Murine motor neuron disease (the wobbler mouse): degeneration and regeneration of the lower motor neuron. Brain. 1982, 105: 811-834. 10.1093/brain/105.4.811.
Jäger S, Bucci C, Tanida I, Ueno T, Kominami E, Saftig P, Eskelinen EL: Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci. 2004, 117: 4837-48.
Li L, Zhang X, Le W: Altered macroautophagy in the spinal cord of SOD1 mutant mice. Autophagy. 2008, 4: 290-3.
Perez-Victoria FJ, Mardones GA, Bonifacino JS: Requirement of the Human GARP Complex for Mannose 6-phosphate-receptor-dependent Sorting of Cathepsin D to Lysosomes. Mol Biol Cell. 2008, 19: 2350-62. 10.1091/mbc.E07-11-1189.
Burman JL, Hamlin JN, McPherson PS: Scyl1 regulates Golgi morphology. PLoS One. 2010, 5: e9537-10.1371/journal.pone.0009537.
Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, Hung WY, Ouahchi K, Yan J, Azim AC, Cole N, Gascon G, Yagmour A, Ben-Hamida M, Pericak-Vance M, Hentati F, Siddique T: The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet. 2001, 29: 160-5. 10.1038/ng1001-160.
Otomo A, Hadano S, Okada T, Mizumura H, Kunita R, Nishijima H, Showguchi-Miyata J, Yanagisawa Y, Kohiki E, Suga E, Yasuda M, Osuga H, Nishimoto T, Narumiya S, Ikeda JE: ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics. Hum Mol Genet. 2003, 12: 1671-87. 10.1093/hmg/ddg184.
Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, Kok F, Oliveira JR, Gillingwater T, Webb J, Skehel P, Zatz M: A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet. 2004, 75: 822-31. 10.1086/425287.
Puls I, Jonnakuty C, LaMonte BH, Holzbaur EL, Tokito M, Mann E, Floeter MK, Bidus K, Drayna D, Oh SJ, Brown RH, Ludlow CL, Fischbeck KH: Mutant dynactin in motor neuron disease. Nat Genet. 2003, 33: 455-6. 10.1038/ng1123.
Chow CY, Landers JE, Bergren SK, Sapp PC, Grant AE, Jones JM, Everett L, Lenk GM, McKenna-Yasek DM, Weisman LS, Figlewicz D, Brown RH, Meisler MH: Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. Am J Hum Genet. 2009, 84: 85-88. 10.1016/j.ajhg.2008.12.010.
Meisler MH, Russ C, Montgomery KT, Greenway M, Ennis S, Hardiman O, Figlewicz DA, Quenneville NR, Conibear E, Brown RH: Evaluation of the Golgi trafficking protein VPS54 (wobbler) as a candidate for ALS. Amyotroph Lateral Scler. 2008, 9: 141-148. 10.1080/17482960801934403.
Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX, et al.: Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science. 1994, 264: 1772-5. 10.1126/science.8209258.
Forssmann WG, Ito S, Weihe E, Aoki A, Dym M, Fawcett DW: An improved perfusion fixation method for the testis. Anat Rec. 1977, 188: 307-314. 10.1002/ar.1091880304.
Sambrook DWRJ: Molecular Cloning: A laboratory manual. 2001, New York: Cold Spring Harbor Laboratory Press, 3