Loss of parkin promotes lipid rafts-dependent endocytosis through accumulating caveolin-1: implications for Parkinson’s disease

Molecular Neurodegeneration

Sang Myun Park¹  Hwan-Myung Kim³  Ilo Jou¹  Eun-Hye Joe¹  Seo-Jun Kang¹  Cheol-Ho Heo³  Yu Ree Choi¹  Seon-Heui Cha² 

[1] Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Korea;Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea;Department of Chemistry, Ajou University, Suwon, Korea

关键词: Cell-to-cell transmission;    Endocytosis;    Caveolin-1;    Parkin;   

Others  :  1234538
DOI  :  10.1186/s13024-015-0060-5

 received in 2015-09-25, accepted in 2015-11-23,  发布年份 2015

【 摘 要 】

Background

Parkinson’s disease (PD) is characterized by progressive loss of midbrain dopaminergic neurons, resulting in motor dysfunctions. While most PD is sporadic in nature, a significant subset can be linked to either autosomal dominant or recessive mutations. PARK2, encoding the E3 ubiquitin ligase, parkin, is the most frequently mutated gene in autosomal recessive early onset PD. It has recently been reported that PD-associated gene products such as PINK1, α-synuclein, LRRK2, and DJ-1, as well as parkin associate with lipid rafts, suggesting that the dysfunction of these proteins in lipid rafts may be a causal factor of PD. Therefore here, we examined the relationship between lipid rafts-related proteins and parkin.

Results

We identified caveolin-1 (cav-1), which is one of the major constituents of lipid rafts at the plasma membrane, as a substrate of parkin. Loss of parkin function was found to disrupt the ubiquitination and degradation of cav-1, resulting in elevated cav-1 protein level in cells. Moreover, the total cholesterol level and membrane fluidity was altered by parkin deficiency, causing dysregulation of lipid rafts-dependent endocytosis. Further, cell-to-cell transmission of α-synuclein was facilitated by parkin deficiency.

Conclusions

Our results demonstrate that alterations in lipid rafts by the loss of parkin via cav-1 may be a causal factor of PD, and cav-1 may be a novel therapeutic target for PD.

【 授权许可】

   
2015 Cha et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

Fig. 6.

Figure 3.

【 参考文献 】

• [1]Lees AJ, Hardy J, Revesz T. Parkinson’s disease. Lancet. 2009; 373:2055-2066.
• [2]Corti O, Lesage S, Brice A. What genetics tells us about the causes and mechanisms of Parkinson’s disease. Physiol Rev. 2011; 91:1161-1218.
• [3]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;106:13010–5.
• [4]Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ, et al. Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science. 2012;338:949–53.
• [5]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;72:57–71.
• [6]Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet. 2000;25:302–5.
• [7]Puschmann A. Monogenic Parkinson’s disease and parkinsonism: clinical phenotypes and frequencies of known mutations. Parkinsonism Relat Disord. 2013; 19:407-415.
• [8]Dawson TM, Dawson VL. Parkin plays a role in sporadic Parkinson’s disease. Neurodegener Dis. 2014; 13:69-71.
• [9]Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM. Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci U S A. 2000; 97:13354-13359.
• [10]Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell. 2001; 105:891-902.
• [11]Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, et al. Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med. 2001;7:1144–50.
• [12]Shin JH, Ko HS, Kang H, Lee Y, Lee YI, Pletinkova O, et al. PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson’s disease. Cell. 2011;144:689–702.
• [13]Fallon L, Moreau F, Croft BG, Labib N, Gu WJ, Fon EA. Parkin and CASK/LIN-2 associate via a PDZ-mediated interaction and are co-localized in lipid rafts and postsynaptic densities in brain. J Biol Chem. 2002; 277:486-491.
• [14]Shimura H, Hattori N, Kubo S, Yoshikawa M, Kitada T, Matsumine H, et al. Immunohistochemical and subcellular localization of Parkin protein: absence of protein in autosomal recessive juvenile Parkinsonism patients. Ann Neurol. 1999;45:668–72.
• [15]Kubo SI, Kitami T, Noda S, Shimura H, Uchiyama Y, Asakawa S, et al. Parkin is associated with cellular vesicles. J Neurochem. 2001;78:42–54.
• [16]Korade Z, Kenworthy AK. Lipid rafts, cholesterol, and the brain. Neuropharmacology. 2008; 55:1265-1273.
• [17]Simons K, Ikonen E. Functional rafts in cell membranes. Nature. 1997; 387:569-572.
• [18]Quest AF, Leyton L, Parraga M. Caveolins, caveolae, and lipid rafts in cellular transport, signaling, and disease. Biochem Cell Biol. 2004; 82:129-144.
• [19]Schengrund CL. Lipid rafts: keys to neurodegeneration. Brain Res Bull. 2010; 82:7-17.
• [20]Sonnino S, Aureli M, Grassi S, Mauri L, Prioni S, Prinetti A. Lipid Rafts in Neurodegeneration and Neuroprotection. Mol Neurobiol. 2014; 50:130-48.
• [21]Fortin DL, Troyer MD, Nakamura K, Kubo S, Anthony MD, Edwards RH. Lipid rafts mediate the synaptic localization of alpha-synuclein. J Neurosci. 2004; 24:6715-6723.
• [22]Silvestri L, Caputo V, Bellacchio E, Atorino L, Dallapiccola B, Valente EM, et al. Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive Parkinsonism. Hum Mol Genet. 2005;14:3477–92.
• [23]Hatano T, Kubo S, Imai S, Maeda M, Ishikawa K, Mizuno Y, et al. Leucine-rich repeat kinase 2 associates with lipid rafts. Hum Mol Genet. 2007;16:678–90.
• [24]Kim KS, Kim JS, Park JY, Suh YH, Jou I, Joe EH, et al. DJ-1 associates with lipid rafts by palmitoylation and regulates lipid rafts-dependent endocytosis in astrocytes. Hum Mol Genet. 2013;22:4805–17.
• [25]Zlatkine P, Mehul B, Magee AI. Retargeting of cytosolic proteins to the plasma membrane by the Lck protein tyrosine kinase dual acylation motif. J Cell Sci. 1997;110(Pt 5):673–9.
• [26]Hayer A, Stoeber M, Ritz D, Engel S, Meyer HH, Helenius A. Caveolin-1 is ubiquitinated and targeted to intralumenal vesicles in endolysosomes for degradation. J Cell Biol. 2010; 191:615-629.
• [27]Kirchner P, Bug M, Meyer H. Ubiquitination of the N-terminal region of caveolin-1 regulates endosomal sorting by VCP/p97. J Biol Chem. 2013; 288:7363-72.
• [28]Ikonen E, Parton RG. Caveolins and cellular cholesterol balance. Traffic. 2000; 1:212-217.
• [29]Smart EJ, Ying Y, Donzell WC, Anderson RG. A role for caveolin in transport of cholesterol from endoplasmic reticulum to plasma membrane. J Biol Chem. 1996; 271:29427-29435.
• [30]Kim HM, Choo HJ, Jung SY, Ko YG, Park WH, Jeon SJ, et al. A two-photon fluorescent probe for lipid raft imaging: C-laurdan. Chembiochem. 2007;8:553–9.
• [31]Singh RD, Puri V, Valiyaveettil JT, Marks DL, Bittman R, Pagano RE. Selective caveolin-1-dependent endocytosis of glycosphingolipids. Mol Biol Cell. 2003; 14:3254-3265.
• [32]Spector AA, Yorek MA. Membrane lipid composition and cellular function. J Lipid Res. 1985; 26:1015-1035.
• [33]Marks DL, Singh RD, Choudhury A, Wheatley CL, Pagano RE. Use of fluorescent sphingolipid analogs to study lipid transport along the endocytic pathway. Methods. 2005; 36:186-195.
• [34]Maxfield FR, McGraw TE. Endocytic recycling. Nat Rev Mol Cell Biol. 2004; 5:121-132.
• [35]Widera A, Norouziyan F, Shen WC. Mechanisms of TfR-mediated transcytosis and sorting in epithelial cells and applications toward drug delivery. Adv Drug Deliv Rev. 2003; 55:1439-1466.
• [36]Park JY, Kim KS, Lee SB, Ryu JS, Chung KC, Choo YK, et al. On the mechanism of internalization of alpha-synuclein into microglia: roles of ganglioside GM1 and lipid raft. J Neurochem. 2009;110:400–11.
• [37]Kim KS, Choi YR, Park JY, Lee JH, Kim DK, Lee SJ, et al. Proteolytic cleavage of extracellular alpha-synuclein by plasmin: implications for Parkinson disease. J Biol Chem. 2012;287:24862–72.
• [38]Martin V, Fabelo N, Santpere G, Puig B, Marin R, Ferrer I, et al. Lipid alterations in lipid rafts from Alzheimer’s disease human brain cortex. J Alzheimers Dis. 2010;19:489–502.
• [39]Fabelo N, Martin V, Santpere G, Marin R, Torrent L, Ferrer I, et al. Severe alterations in lipid composition of frontal cortex lipid rafts from Parkinson’s disease and incidental Parkinson’s disease. Mol Med. 2011;17:1107–18.
• [40]Chadwick W, Brenneman R, Martin B, Maudsley S. Complex and multidimensional lipid raft alterations in a murine model of Alzheimer’s disease. Int J Alzheimers Dis. 2010;2010:604792.
• [41]Zhai J, Strom AL, Kilty R, Venkatakrishnan P, White J, Everson WV, et al. Proteomic characterization of lipid raft proteins in amyotrophic lateral sclerosis mouse spinal cord. FEBS J. 2009;276:3308–23.
• [42]Lajoie P, Nabi IR. Lipid rafts, caveolae, and their endocytosis. Int Rev Cell Mol Biol. 2010; 282:135-163.
• [43]Stern CM, Mermelstein PG. Caveolin regulation of neuronal intracellular signaling. Cell Mol Life Sci. 2010; 67:3785-3795.
• [44]Liu P, Rudick M, Anderson RG. Multiple functions of caveolin-1. J Biol Chem. 2002; 277:41295-41298.
• [45]Cohen AW, Hnasko R, Schubert W, Lisanti MP. Role of caveolae and caveolins in health and disease. Physiol Rev. 2004; 84:1341-1379.
• [46]Gaudreault SB, Dea D, Poirier J. Increased caveolin-1 expression in Alzheimer’s disease brain. Neurobiol Aging. 2004; 25:753-759.
• [47]Park WY, Park JS, Cho KA, Kim DI, Ko YG, Seo JS, et al. Up-regulation of caveolin attenuates epidermal growth factor signaling in senescent cells. J Biol Chem. 2000;275:20847–52.
• [48]Kang MJ, Chung YH, Hwang CI, Murata M, Fujimoto T, Mook-Jung IH, et al. Caveolin-1 upregulation in senescent neurons alters amyloid precursor protein processing. Exp Mol Med. 2006;38:126–33.
• [49]Volonte D, Zhang K, Lisanti MP, Galbiati F. Expression of caveolin-1 induces premature cellular senescence in primary cultures of murine fibroblasts. Mol Biol Cell. 2002; 13:2502-2517.
• [50]Head BP, Peart JN, Panneerselvam M, Yokoyama T, Pearn ML, Niesman IR, et al. Loss of caveolin-1 accelerates neurodegeneration and aging. PLoS One. 2010;5:e15697.
• [51]Park DS, Cohen AW, Frank PG, Razani B, Lee H, Williams TM, et al. Caveolin-1 null (-/-) mice show dramatic reductions in life span. Biochemistry. 2003;42:15124–31.
• [52]Cho KA, Park SC. Caveolin-1 as a prime modulator of aging: a new modality for phenotypic restoration? Mech Ageing Dev. 2005; 126:105-110.
• [53]Collier TJ, Kanaan NM, Kordower JH. Ageing as a primary risk factor for Parkinson’s disease: evidence from studies of non-human primates. Nat Rev Neurosci. 2011; 12:359-366.
• [54]Rodriguez M, Rodriguez-Sabate C, Morales I, Sanchez A, Sabate M. Parkinson’s disease as a result of aging. Aging Cell. 2015; 14:293-308.
• [55]Madeira A, Yang J, Zhang X, Vikeved E, Nilsson A, Andren PE, et al. Caveolin-1 interacts with alpha-synuclein and mediates toxic actions of cellular alpha-synuclein overexpression. Neurochem Int. 2011;59:280–9.
• [56]Hashimoto M, Takenouchi T, Rockenstein E, Masliah E. Alpha-synuclein up-regulates expression of caveolin-1 and down-regulates extracellular signal-regulated kinase activity in B103 neuroblastoma cells: role in the pathogenesis of Parkinson’s disease. J Neurochem. 2003; 85:1468-1479.
• [57]Toselli M, Biella G, Taglietti V, Cazzaniga E, Parenti M. Caveolin-1 expression and membrane cholesterol content modulate N-type calcium channel activity in NG108-15 cells. Biophys J. 2005; 89:2443-2457.
• [58]Martin MG, Pfrieger F, Dotti CG. Cholesterol in brain disease: sometimes determinant and frequently implicated. EMBO Rep. 2014; 15:1036-1052.
• [59]Trushina E, Singh RD, Dyer RB, Cao S, Shah VH, Parton RG, et al. Mutant huntingtin inhibits clathrin-independent endocytosis and causes accumulation of cholesterol in vitro and in vivo. Hum Mol Genet. 2006;15:3578–91.
• [60]Trushina E, Canaria CA, Lee DY, McMurray CT. Loss of caveolin-1 expression in knock-in mouse model of Huntington’s disease suppresses pathophysiology in vivo. Hum Mol Genet. 2014; 23:129-144.
• [61]Fabelo N, Martin V, Marin R, Moreno D, Ferrer I, Diaz M. Altered lipid composition in cortical lipid rafts occurs at early stages of sporadic Alzheimer’s disease and facilitates APP/BACE1 interactions. Neurobiol Aging. 2014; 35:1801-1812.
• [62]Fabelo N, Martin V, Marin R, Santpere G, Aso E, Ferrer I, et al. Evidence for premature lipid raft aging in APP/PS1 double-transgenic mice, a model of familial Alzheimer disease. J Neuropathol Exp Neurol. 2012;71:868–81.
• [63]Fallon L, Belanger CM, Corera AT, Kontogiannea M, Regan-Klapisz E, Moreau F, et al. A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling. Nat Cell Biol. 2006;8:834–42.
• [64]Sigismund S, Woelk T, Puri C, Maspero E, Tacchetti C, Transidico P, et al. Clathrin-independent endocytosis of ubiquitinated cargos. Proc Natl Acad Sci U S A. 2005;102:2760–5.
• [65]Agelaki S, Spiliotaki M, Markomanolaki H, Kallergi G, Mavroudis D, Georgoulias V, et al. Caveolin-1 regulates EGFR signaling in MCF-7 breast cancer cells and enhances gefitinib-induced tumor cell inhibition. Cancer Biol Ther. 2009;8:1470–7.
• [66]Frost B, Diamond MI. Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci. 2010;11:155–9.
• [67]Goedert M, Clavaguera F, Tolnay M. The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci. 2010; 33:317-325.
• [68]Petrucelli L, O’Farrell C, Lockhart PJ, Baptista M, Kehoe K, Vink L, et al. Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron. 2002;36:1007–19.
• [69]Oluwatosin-Chigbu Y, Robbins A, Scott CW, Arriza JL, Reid JD, Zysk JR. Parkin suppresses wild-type alpha-synuclein-induced toxicity in SHSY-5Y cells. Biochem Biophys Res Commun. 2003; 309:679-684.
• [70]Lo Bianco C, Schneider BL, Bauer M, Sajadi A, Brice A, Iwatsubo T, et al. Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson’s disease. Proc Natl Acad Sci USA. 2004;101:17510–5.
• [71]Lu XH, Fleming SM, Meurers B, Ackerson LC, Mortazavi F, Lo V, et al. Bacterial artificial chromosome transgenic mice expressing a truncated mutant parkin exhibit age-dependent hypokinetic motor deficits, dopaminergic neuron degeneration, and accumulation of proteinase K-resistant alpha-synuclein. J Neurosci. 2009;29:1962–76.
• [72]Bae EJ, Yang NY, Song M, Lee CS, Lee JS, Jung BC, et al. Glucocerebrosidase depletion enhances cell-to-cell transmission of alpha-synuclein. Nat Commun. 2014;5:4755.
• [73]Lotharius J, Brundin P. Pathogenesis of Parkinson’s disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci. 2002; 3:932-942.
• [74]Ciechanover A, Brundin P. The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron. 2003; 40:427-446.
• [75]von Coelln R, Thomas B, Andrabi SA, Lim KL, Savitt JM, Saffary R, et al. Inclusion body formation and neurodegeneration are parkin independent in a mouse model of alpha-synucleinopathy. J Neurosci. 2006;26:3685–96.
• [76]Kim KY, Stevens MV, Akter MH, Rusk SE, Huang RJ, Cohen A, et al. Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells. J Clin Invest. 2011;121:3701–12.
• [77]Zhang C, Lin M, Wu R, Wang X, Yang B, Levine AJ, et al. Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc Natl Acad Sci U S A. 2011;108:16259–64.
• [78]Gong Y, Zack TI, Morris LG, Lin K, Hukkelhoven E, Raheja R, et al. Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins. Nat Genet. 2014;46:588–94.
• [79]Sotgia F, Martinez-Outschoorn UE, Howell A, Pestell RG, Pavlides S, Lisanti MP. Caveolin-1 and cancer metabolism in the tumor microenvironment: markers, models, and mechanisms. Annu Rev Pathol. 2012; 7:423-467.
• [80]Torashima T, Okoyama S, Nishizaki T, Hirai H. In vivo transduction of murine cerebellar Purkinje cells by HIV-derived lentiviral vectors. Brain Res. 2006; 1082:11-22.
• [81]Dibya D, Arora N, Smith EA. Noninvasive measurements of integrin microclustering under altered membrane cholesterol levels. Biophys J. 2010; 99:853-861.