SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation

Molecular Neurodegeneration

Justin J. Yerbury⁶  Neil R. Cashman⁴  Mark R. Wilson⁶  Lezanne Ooi⁶  Bradley J. Turner³  Christopher M. Dobson⁷  Heath Ecroyd⁶  Danny M. Hatters²  Kara L. Vine⁶  Gilles Guillemin⁵  Monique Bax⁶  Dzung Do-Ha⁶  Elise M. Stewart¹  Lisa Corcoran⁶  Jay F. Pundavela⁶  Rafaa Zeineddine⁶ 

[1]Intelligent Polymer Research Institute, University of Wollongong, Wollongong 2522Australia

[2]Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville 3010Australia

[3]Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3010Australia

[4]Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, University of British Columbia, Vancouver V6T 2B5Canada

[5]Australian School for Advanced Medicine, Macquarie University, Sydney 2109Australia

[6]School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong 2522Australia

[7]Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK

关键词: Macropinocytosis;    Transmission;    Protein aggregation;   

Others  :  1230391
DOI  :  10.1186/s13024-015-0053-4

 received in 2015-03-29, accepted in 2015-10-23,  发布年份 2015

【 摘 要 】

Background

Amyotrophic Lateral Sclerosis is characterized by a focal onset of symptoms followed by a progressive spread of pathology that has been likened to transmission of infectious prions. Cell-to-cell transmission of SOD1 protein aggregates is dependent on fluid-phase endocytosis pathways, although the precise molecular mechanisms remain to be elucidated.

Results

We demonstrate in this paper that SOD1 aggregates interact with the cell surface triggering activation of Rac1 and subsequent membrane ruffling permitting aggregate uptake via stimulated macropinocytosis. In addition, other protein aggregates, including those associated with neurodegenerative diseases (TDP-43, Htt _ex1 46Q, α-synuclein) also trigger membrane ruffling to gain entry into the cell. Aggregates are able to rupture unstructured macropinosomes to enter the cytosol allowing propagation of aggregation to proceed.

Conclusion

Thus, we conclude that in addition to basic proteostasis mechanisms, pathways involved in the activation of macropinocytosis are key determinants in the spread of pathology in these misfolding diseases.

【 授权许可】

   
2015 Zeineddine et al.

【 图 表 】

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【 参考文献 】

• [1]Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati D et al.. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993; 362(6415):59-62.
• [2]Renton AE, Chio A, Traynor BJ. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci. 2014; 17(1):17-23.
• [3]Aggarwal A, Nicholson G. Detection of preclinical motor neurone loss in SOD1 mutation carriers using motor unit number estimation. J Neurol Neurosurg Psychiatry. 2002; 73(2):199-201.
• [4]Shaw PJ. Toxicity of CSF in motor neurone disease: a potential route to neuroprotection. Brain. 2002; 125(Pt 4):693-694.
• [5]Brettschneider J, Del Tredici K, Irwin DJ, Grossman M, Robinson JL, Toledo L et al.. Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD). Acta Neuropathol. 2014; 127(3):423-439.
• [6]Ravits JM, La Spada AR. ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology. 2009; 73(10):805-811.
• [7]Chiti F, Dobson CM. Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem. 2006; 75:333-366.
• [8]Knowles TP, Vendruscolo M, Dobson CM. The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol. 2014; 15(6):384-396.
• [9]Pasinelli P, Brown RH. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci. 2006; 7(9):710-723.
• [10]Hortschansky P, Schroeckh V, Christopeit T, Zandomeneghi G, Fandrich M. The aggregation kinetics of Alzheimer's beta-amyloid peptide is controlled by stochastic nucleation. Protein Sci. 2005; 14(7):1753-1759.
• [11]Knowles TP, Waudby CA, Devlin GL, Cohen SI, Aguzzi A, Vendruscolo M et al.. An analytical solution to the kinetics of breakable filament assembly. Science. 2009; 326(5959):1533-1537.
• [12]Knowles TP, White DA, Abate AR, Agresti JJ, Cohen SI, Sperling RA et al.. Observation of spatial propagation of amyloid assembly from single nuclei. Proc Natl Acad Sci U S A. 2011; 108(36):14746-14751.
• [13]Cohen SI, Linse S, Luheshi LM, Hellstrand E, White DA, Rajah L et al.. Proliferation of amyloid-beta42 aggregates occurs through a secondary nucleation mechanism. Proc Natl Acad Sci U S A. 2013; 110(24):9758-9763.
• [14]Munch C, O'Brien J, Bertolotti A. Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proc Natl Acad Sci U S A. 2011; 108(9):3548-3553.
• [15]Ayers JI, Fromholt S, Koch M, DeBosier A, McMahon B, Xu G et al.. Experimental transmissibility of mutant SOD1 motor neuron disease. Acta Neuropathol. 2014; 128(6):791-803.
• [16]Grad LI, Yerbury JJ, Turner BJ, Guest WC, Pokrishevsky E, O'Neill MA et al.. Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms. Proc Natl Acad Sci U S A. 2014; 111(9):3620-3625.
• [17]Sundaramoorthy V, Walker AK, Yerbury J, Soo KY, Farg MA, Hoang V et al.. Extracellular wildtype and mutant SOD1 induces ER-Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells. Cell Mol Life Sci. 2013; 70(21):4181-4195.
• [18]Swanson JA, Watts C. Macropinocytosis. Trends Cell Biol. 1995; 5(11):424-428.
• [19]Mercer J, Helenius A. Virus entry by macropinocytosis. Nat Cell Biol. 2009; 11(5):510-520.
• [20]Mercer J, Helenius A. Gulping rather than sipping: macropinocytosis as a way of virus entry. Curr Opin Microbiol. 2012; 15(4):490-499.
• [21]Kalia M, Khasa R, Sharma M, Nain M, Vrati S. Japanese encephalitis virus infects neuronal cells through a clathrin-independent endocytic mechanism. J Virol. 2013; 87(1):148-162.
• [22]Conner SD, Schmid SL. Regulated portals of entry into the cell. Nature. 2003; 422(6927):37-44.
• [23]Holmes BB, DeVos SL, Kfoury N, Li M, Jacks R, Yanamandra K et al.. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci U S A. 2013; 110(33):E3138-E3147.
• [24]Wadia JS, Schaller M, Williamson RA, Dowdy SF. Pathologic prion protein infects cells by lipid-raft dependent macropinocytosis. PLoS One. 2008; 3(10): Article ID e3314
• [25]Ivanov AI. Pharmacological inhibition of endocytic pathways: is it specific enough to be useful? Methods Mol Biol. 2008; 440:15-33.
• [26]Yerbury JJ, Gower D, Vanags L, Roberts K, Lee JA, Ecroyd H. The small heat shock proteins alphaB-crystallin and Hsp27 suppress SOD1 aggregation in vitro. Cell Stress Chaperones. 2013; 18(2):251-257.
• [27]Damiano S, Petrozziello T, Ucci V, Amente S, Santillo M, Mondola P. Cu-Zn superoxide dismutase activates muscarinic acetylcholine M1 receptor pathway in neuroblastoma cells. Mol Cell Neurosci. 2013; 52:31-37.
• [28]Turner BJ, Atkin JD, Farg MA, Zang DW, Rembach A, Lopes EC et al.. Impaired extracellular secretion of mutant superoxide dismutase 1 associates with neurotoxicity in familial amyotrophic lateral sclerosis. J Neurosci. 2005; 25(1):108-117.
• [29]Grad LI, Guest WC, Yanai A, Pokrishevsky E, O'Neill MA, Gibbs E et al.. Intermolecular transmission of superoxide dismutase 1 misfolding in living cells. Proc Natl Acad Sci U S A. 2011; 108(39):16398-16403.
• [30]Graffmo KS, Forsberg K, Bergh J, Birve A, Zetterstrom P, Andersen PM et al.. Expression of wild-type human superoxide dismutase-1 in mice causes amyotrophic lateral sclerosis. Hum Mol Genet. 2013; 22(1):51-60.
• [31]Deng HX, Shi Y, Furukawa Y, Zhai H, Fu R, Liu E et al.. Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria. Proc Natl Acad Sci U S A. 2006; 103(18):7142-7147.
• [32]Nizard P, Tetley S, Le Drean Y, Watrin T, Le Goff P, Wilson MR et al.. Stress-induced retrotranslocation of clusterin/ApoJ into the cytosol. Traffic. 2007; 8(5):554-565.
• [33]Schneider D, Greb C, Koch A, Straube T, Elli A, Delacour D et al.. Trafficking of galectin-3 through endosomal organelles of polarized and non-polarized cells. Eur J Cell Biol. 2010; 89(11):788-798.
• [34]Freeman D, Cedillos R, Choyke S, Lukic Z, McGuire K, Marvin S et al.. Alpha-synuclein induces lysosomal rupture and cathepsin dependent reactive oxygen species following endocytosis. PLoS One. 2013; 8(4): Article ID e62143
• [35]Maier O, Marvin SA, Wodrich H, Campbell EM, Wiethoff CM. Spatiotemporal dynamics of adenovirus membrane rupture and endosomal escape. J Virol. 2012; 86(19):10821-10828.
• [36]Milanesi L, Sheynis T, Xue WF, Orlova EV, Hellewell AL, Jelinek R et al.. Direct three-dimensional visualization of membrane disruption by amyloid fibrils. Proc Natl Acad Sci U S A. 2012; 109(50):20455-20460.
• [37]Kolpak AL, Jiang J, Guo D, Standley C, Bellve K, Fogarty K et al.. Negative guidance factor-induced macropinocytosis in the growth cone plays a critical role in repulsive axon turning. J Neurosci. 2009; 29(34):10488-10498.
• [38]Kulig M, Ecroyd H. The small heat-shock protein alphaB-crystallin uses different mechanisms of chaperone action to prevent the amorphous versus fibrillar aggregation of alpha-lactalbumin. Biochem J. 2012; 448(3):343-352.
• [39]Munch J, Rucker E, Standker L, Adermann K, Goffinet C, Schindler M et al.. Semen-derived amyloid fibrils drastically enhance HIV infection. Cell. 2007; 131(6):1059-1071.
• [40]Buell AK, Galvagnion C, Gaspar R, Sparr E, Vendruscolo M, Knowles TP et al.. Solution conditions determine the relative importance of nucleation and growth processes in alpha-synuclein aggregation. Proc Natl Acad Sci U S A. 2014; 111(21):7671-7676.
• [41]Harraz MM, Marden JJ, Zhou W, Zhang Y, Williams A, Sharov VS et al.. SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model. J Clin Invest. 2008; 118(2):659-670.
• [42]Sanchez EG, Quintas A, Perez-Nunez D, Nogal M, Barroso S, Carrascosa AL et al.. African swine fever virus uses macropinocytosis to enter host cells. PLoS Pathog. 2012; 8(6): Article ID e1002754
• [43]Swanson JA. Phorbol esters stimulate macropinocytosis and solute flow through macrophages. J Cell Sci. 1989; 94(Pt 1):135-142.
• [44]Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A et al.. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009; 11(7):909-913.
• [45]Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L et al.. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A. 2009; 106(31):13010-13015.
• [46]Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature. 2013; 501(7465):45-51.
• [47]Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ et al.. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med. 2008; 14(5):501-503.
• [48]Ren PH, Lauckner JE, Kachirskaia I, Heuser JE, Melki R, Kopito RR. Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat Cell Biol. 2009; 11(2):219-225.
• [49]Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM, Stieber A et al.. Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron. 2011; 72(1):57-71.
• [50]Roberts K, Zeineddine R, Corcoran L, Li W, Campbell IL, Yerbury JJ. Extracellular aggregated Cu/Zn superoxide dismutase activates microglia to give a cytotoxic phenotype. Glia. 2013; 61(3):409-419.
• [51]Medeiros LA, Khan T, El Khoury JB, Pham CL, Hatters DM, Howlett GJ et al.. Fibrillar amyloid protein present in atheroma activates CD36 signal transduction. J Biol Chem. 2004; 279(11):10643-10648.
• [52]Cashman NR, Durham HD, Blusztajn JK, Oda K, Tabira T, Shaw IT. Neuroblastoma x Spinal Cord (NSC) Hybrid Cell Lines Resemble Developing Motor Neurons. Dev Dynam. 1992; 194:209-221.
• [53]Muller FJ, Schuldt BM, Williams R, Mason D, Altun G, Papapetrou EP et al.. A bioinformatic assay for pluripotency in human cells. Nat Methods. 2011; 8(4):315-317.
• [54]Bilican B, Livesey MR, Haghi G, Qiu J, Burr K, Siller R et al.. Physiological normoxia and absence of EGF is required for the long-term propagation of anterior neural precursors from human pluripotent cells. PLoS One. 2014; 9(1): Article ID e85932
• [55]Arber S, Han B, Mendelsohn M, Smith M, Jessell TM, Sockanathan S. Requirement for the homeobox gene Hb9 in the consolidation of motor neuron identity. Neuron. 1999; 23(4):659-674.
• [56]Lindberg MJ, Tibell L, Oliveberg M. Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: Decreased stability of the apo state. Proc Natl Acad Sci U S A. 2002; 99(26):16607-16612.
• [57]Olshina MA, Angley LM, Ramdzan YM, Tang J, Bailey MF, Hill AF et al.. Tracking mutant huntingtin aggregation kinetics in cells reveals three major populations that include an invariant oligomer pool. J Biol Chem. 2010; 285(28):21807-21816.
• [58]Johnson BS, Snead D, Lee JJ, McCaffery JM, Shorter J, Gitler AD. TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J Biol Chem. 2009; 284(30):20329-20339.
• [59]Aquilina JA, Shrestha S, Morris AM, Ecroyd H. Structural and functional aspects of hetero-oligomers formed by the small heat shock proteins alphaB-crystallin and HSP27. J Biol Chem. 2013; 288(19):13602-13609.