nach oben

Erschienen in:

01.03.2013 | Original Paper

VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy

verfasst von: Nivetha Ramachandran, Iulia Munteanu, Peixiang Wang, Alessandra Ruggieri, Jennifer J. Rilstone, Nyrie Israelian, Taline Naranian, Paul Paroutis, Ray Guo, Zhi-Ping Ren, Ichizo Nishino, Brigitte Chabrol, Jean-Francois Pellissier, Carlo Minetti, Bjarne Udd, Michel Fardeau, Chetankumar S. Tailor, Don J. Mahuran, John T. Kissel, Hannu Kalimo, Nicolas Levy, Morris F. Manolson, Cameron A. Ackerley, Berge A. Minassian

Erschienen in: Acta Neuropathologica | Ausgabe 3/2013

Einloggen, um Zugang zu erhalten

Abstract

X-linked Myopathy with Excessive Autophagy (XMEA) is a childhood onset disease characterized by progressive vacuolation and atrophy of skeletal muscle. We show that XMEA is caused by hypomorphic alleles of the VMA21 gene, that VMA21 is the diverged human ortholog of the yeast Vma21p protein, and that like Vma21p, VMA21 is an essential assembly chaperone of the vacuolar ATPase (V-ATPase), the principal mammalian proton pump complex. Decreased VMA21 raises lysosomal pH which reduces lysosomal degradative ability and blocks autophagy. This reduces cellular free amino acids which leads to downregulation of the mTORC1 pathway, and consequent increased macroautophagy resulting in proliferation of large and ineffective autolysosomes that engulf sections of cytoplasm, merge, and vacuolate the cell. Our results uncover a novel mechanism of disease, namely macroautophagic overcompensation leading to cell vacuolation and tissue atrophy.

Nur mit Berechtigung zugänglich

Beugnet A, Tee AR, Taylor PM, Proud CG (2003) Regulation of targets of mTOR (mammalian target of rapamycin) signalling by intracellular amino acid availability. Biochem J 372:555–566PubMedCrossRef

Blommaart EF, Luiken JJ, Blommaart PJ, van Woerkom GM, Meijer AJ (1995) Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem 270:2320–2326PubMedCrossRef

Brummelkamp TR, Bernards R, Agami R (2002) A system for stable expression of short interfering RNAs in mammalian cells. Science 296:550–553PubMedCrossRef

Cao Y, Klionsky DJ (2007) Physiological functions of Atg6/Beclin 1: a unique autophagy-related protein. Cell Res 17:839–849PubMedCrossRef

Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:1292–1295PubMedCrossRef

Demaurex N, Furuya W, D’Souza S, Bonifacino JS, Grinstein S (1998) Mechanism of acidification of the trans-Golgi network (TGN). In situ measurements of pH using retrieval of TGN38 and furin from the cell surface. J Biol Chem 273:2044–2051PubMedCrossRef

Drose S, Altendorf K (1997) Bafilomycins and concanamycins as inhibitors of V-ATPases and P-ATPases. J Exp Biol 200:1–8PubMed

Forgac M (2007) Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nat Rev Mol Cell Biol 8:917–929PubMedCrossRef

Frattini A, Orchard PJ, Sobacchi C et al (2000) Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet 25:343–346PubMedCrossRef

10.

Fukuda K, Hirai Y, Yoshida H, Nakajima T, Usui T (1982) Free amino acid content of lymphocytes and granulocytes compared. Clin Chem 28:1758–1761PubMed

11.

Huss M, Sasse F, Kunze B (2005) Archazolid and apicularen: novel specific V-ATPase inhibitors. BMC Biochem 6:13PubMedCrossRef

12.

Kalimo H, Savontaus ML, Lang H et al (1988) X-linked myopathy with excessive autophagy: a new hereditary muscle disease. Ann Neurol 23:258–265PubMedCrossRef

13.

Karet FE, Finberg KE, Nelson RD et al (1999) Mutations in the gene encoding B1 subunit of H⁺-ATPase cause renal tubular acidosis with sensorineural deafness. Nat Genet 21:84–90PubMedCrossRef

14.

Kornak U, Reynders E, Dimopoulou A et al (2008) Impaired glycosylation and cutis laxa caused by mutations in the vesicular H⁺-ATPase subunit ATP6V0A2. Nat Genet 40:32–34PubMedCrossRef

15.

Kovacs AL, Reith A, Seglen PO (1982) Accumulation of autophagosomes after inhibition of hepatocytic protein degradation by vinblastine, leupeptin or a lysosomotropic amine. Exp Cell Res 137:191–201PubMedCrossRef

16.

Li JB, Goldberg AL (1976) Effects of food deprivation on protein synthesis and degradation in rat skeletal muscles. Am J Physiol 231:441–448PubMed

17.

Malicdan MC, Noguchi S, Nonaka I, Saftig P, Nishino I (2008) Lysosomal myopathies: an excessive build-up in autophagosomes is too much to handle. Neuromuscul Disord 18:521–529PubMedCrossRef

18.

Malkus P, Graham LA, Stevens TH, Schekman R (2004) Role of Vma21p in assembly and transport of the yeast vacuolar ATPase. Mol Biol Cell 15:5075–5091PubMedCrossRef

19.

Mammucari C, Schiaffino S, Sandri M (2008) Downstream of Akt: foxO3 and mTOR in the regulation of autophagy in skeletal muscle. Autophagy 4:524–526PubMed

20.

Massey AC, Kaushik S, Sovak G, Kiffin R, Cuervo AM (2006) Consequences of the selective blockage of chaperone-mediated autophagy. Proc Natl Acad Sci USA 103:5805–5810PubMedCrossRef

21.

Mizushima N (2007) Autophagy: process and function. Genes Dev 21:2861–2873PubMedCrossRef

22.

Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y (2004) In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 15:1101–1111PubMedCrossRef

23.

Munteanu I, Ramachandran N, Mnatzakanian GN et al (2008) Fine-mapping the gene for X-linked myopathy with excessive autophagy. Neurology 71:951–953PubMedCrossRef

24.

Nishino I, Fu J, Tanji K et al (2000) Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406:906–910PubMedCrossRef

25.

Ostenfeld MS, Hoyer-Hansen M, Bastholm L et al (2008) Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation. Autophagy 4:487–499PubMed

26.

Paroutis P, Touret N, Grinstein S (2004) The pH of the secretory pathway: measurement, determinants, and regulation. Physiology (Bethesda) 19:207–215CrossRef

27.

Salvador N, Aguado C, Horst M, Knecht E (2000) Import of a cytosolic protein into lysosomes by chaperone-mediated autophagy depends on its folding state. J Biol Chem 275:27447–27456PubMed

28.

Sandri M (2010) Autophagy in skeletal muscle. FEBS Lett 584:1411–1416PubMedCrossRef

29.

Scornik OA, Howell SK, Botbol V (1997) Protein depletion and replenishment in mice: different roles of muscle and liver. Am J Physiol 273:E1158–E1167PubMed

30.

Scott JA, North ML, Rafii M et al (2011) Asymmetric dimethylarginine is increased in asthma. Am J Respir Crit Care Med 184:779–785PubMedCrossRef

31.

Shacka JJ, Klocke BJ, Shibata M et al (2006) Bafilomycin A1 inhibits chloroquine-induced death of cerebellar granule neurons. Mol Pharmacol 69:1125–1136PubMedCrossRef

32.

Sharma R, Deng H, Leung A, Mahuran D (2001) Identification of the 6-sulfate binding site unique to alpha-subunit-containing isozymes of human beta-hexosaminidase. Biochemistry 40:5440–5446PubMedCrossRef

33.

Stauber WT, Hedge AM, Trout JJ, Schottelius BA (1981) Inhibition of lysosomal function in red and white skeletal muscles by chloroquine. Exp Neurol 71:295–306PubMedCrossRef

34.

Tanaka Y, Guhde G, Suter A et al (2000) Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406:902–906PubMedCrossRef

35.

Taussky HH, Shorr E (1953) A microcolorimetric method for the determination of inorganic phosphorus. J Biol Chem 202:675–685PubMed

36.

Villanova M, Louboutin JP, Chateau D et al (1995) X-linked vacuolated myopathy: complement membrane attack complex on surface membrane of injured muscle fibers. Ann Neurol 37:637–645PubMedCrossRef

37.

Webber JL, Tooze SA (2010) Coordinated regulation of autophagy by p38alpha MAPK through mAtg9 and p38IP. EMBO J 29:27–40PubMedCrossRef

38.

Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM (2011) mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science 334:678–683PubMedCrossRef

Titel: VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy
verfasst von: Nivetha Ramachandran
Iulia Munteanu
Peixiang Wang
Alessandra Ruggieri
Jennifer J. Rilstone
Nyrie Israelian
Taline Naranian
Paul Paroutis
Ray Guo
Zhi-Ping Ren
Ichizo Nishino
Brigitte Chabrol
Jean-Francois Pellissier
Carlo Minetti
Bjarne Udd
Michel Fardeau
Chetankumar S. Tailor
Don J. Mahuran
John T. Kissel
Hannu Kalimo
Nicolas Levy
Morris F. Manolson
Cameron A. Ackerley
Berge A. Minassian
Publikationsdatum: 01.03.2013
Verlag: Springer-Verlag
Erschienen in: Acta Neuropathologica / Ausgabe 3/2013
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-012-1073-6

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Neurologie

23.04.2024 | Demenz | Nachrichten

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy

Abstract

Leitlinien kompakt für die Neurologie

Neu im Fachgebiet Neurologie

Demenzkranke durch Antipsychotika vielfach gefährdet

Parkinson-Therapie im Wandel – aktuelle Leitlinie im Fokus

Auf diese Krankheiten bei Geflüchteten sollten Sie vorbereitet sein

Hustenstiller lindert Agitation bei Alzheimer

Update Neurologie

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2013

Sequence variants in eukaryotic translation initiation factor 4-gamma (eIF4G1) are associated with Lewy body dementia

The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury

Lysosomal storage and advanced senescence in the brain of LAMP-2-deficient Danon disease

Polymorphonuclear neutrophil infiltration into ischemic infarctions: myth or truth?

Inclusions in frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP) and amyotrophic lateral sclerosis (ALS), but not FTLD with FUS proteinopathy (FTLD-FUS), have properties of amyloid

hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations

Leitlinien kompakt für die Neurologie

Neu im Fachgebiet Neurologie

Demenzkranke durch Antipsychotika vielfach gefährdet

Parkinson-Therapie im Wandel – aktuelle Leitlinie im Fokus

Auf diese Krankheiten bei Geflüchteten sollten Sie vorbereitet sein

Hustenstiller lindert Agitation bei Alzheimer

Update Neurologie