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 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2018

Open Access 01-12-2018 | Research article

α-Synuclein accumulation and GBA deficiency due to L444P GBA mutation contributes to MPTP-induced parkinsonism

Authors: Seung Pil Yun, Donghoon Kim, Sangjune Kim, SangMin Kim, Senthilkumar S. Karuppagounder, Seung-Hwan Kwon, Saebom Lee, Tae-In Kam, Suhyun Lee, Sangwoo Ham, Jae Hong Park, Valina L. Dawson, Ted M. Dawson, Yunjong Lee, Han Seok Ko

Published in: Molecular Neurodegeneration | Issue 1/2018

Login to get access

Abstract

Background

Mutations in glucocerebrosidase (GBA) cause Gaucher disease (GD) and increase the risk of developing Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB). Since both genetic and environmental factors contribute to the pathogenesis of sporadic PD, we investigated the susceptibility of nigrostriatal dopamine (DA) neurons in L444P GBA heterozygous knock-in (GBA +/L444P ) mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a selective dopaminergic mitochondrial neurotoxin.

Method

We used GBA +/L444P mice, α-synuclein knockout (SNCA −/− ) mice at 8 months of age, and adeno-associated virus (AAV)-human GBA overexpression to investigate the rescue effect of DA neuronal loss and susceptibility by MPTP. Mitochondrial morphology and functional assay were used to identify mitochondrial defects in GBA +/L444P mice. Motor behavioral test, immunohistochemistry, and HPLC were performed to measure dopaminergic degeneration by MPTP and investigate the relationship between GBA mutation and α-synuclein. Mitochondrial immunostaining, qPCR, and Western blot were also used to study the effects of α-synuclein knockout or GBA overexpression on MPTP-induced mitochondrial defects and susceptibility.

Results

L444P GBA heterozygous mutation reduced GBA protein levels, enzymatic activity and a concomitant accumulation of α-synuclein in the midbrain of GBA +/L444P mice. Furthermore, the deficiency resulted in defects in mitochondria of cortical neurons cultured from GBA +/L444P mice. Notably, treatment with MPTP resulted in a significant loss of dopaminergic neurons and striatal dopaminergic fibers in GBA +/L444P mice compared to wild type (WT) mice. Levels of striatal DA and its metabolites were more depleted in the striatum of GBA +/L444P mice. Behavioral deficits, neuroinflammation, and mitochondrial defects were more exacerbated in GBA +/L444P mice after MPTP treatment. Importantly, MPTP induced PD-like symptoms were significantly improved by knockout of α-synuclein or augmentation of GBA via AAV5-hGBA injection in both WT and GBA +/L444P mice. Intriguingly, the degree of reduction in MPTP induced PD-like symptoms in GBA +/L444P α-synuclein (SNCA) −/− mice was nearly equal to that in SNCA −/− mice after MPTP treatment.

Conclusion

Our results suggest that GBA deficiency due to L444P GBA heterozygous mutation and the accompanying accumulation of α-synuclein render DA neurons more susceptible to MPTP intoxication. Thus, GBA and α-synuclein play dual physiological roles in the survival of DA neurons in response to the mitochondrial dopaminergic neurotoxin, MPTP.
Appendix
Available only for authorised users
Literature
1.
2.
Chaudhuri KR, Healy DG, Schapira AH. National Institute for clinical E: non-motor symptoms of Parkinson's disease: diagnosis and management. Lancet Neurol. 2006;5:235–45.CrossRefPubMed
3.
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. α-synuclein in Lewy bodies. Nature. 1997;388:839–40.CrossRefPubMed
4.
5.
Neumann J, Bras J, Deas E, O'Sullivan SS, Parkkinen L, Lachmann RH, Li A, Holton J, Guerreiro R, Paudel R, et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain. 2009;132:1783–94.CrossRefPubMedPubMedCentral
6.
Tayebi N, Walker J, Stubblefield B, Orvisky E, LaMarca ME, Wong K, Rosenbaum H, Schiffmann R, Bembi B, Sidransky E. Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism? Mol Genet Metab. 2003;79:104–9.CrossRefPubMed
7.
Gan-Or Z, Bar-Shira A, Mirelman A, Gurevich T, Kedmi M, Giladi N, Orr-Urtreger A. LRRK2 and GBA mutations differentially affect the initial presentation of Parkinson disease. Neurogenetics. 2010;11:121–5.CrossRefPubMed
8.
Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009;361:1651–61.CrossRefPubMedPubMedCentral
9.
Gan-Or Z, Giladi N, Rozovski U, Shifrin C, Rosner S, Gurevich T, Bar-Shira A, Orr-Urtreger A. Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology. 2008;70:2277–83.CrossRefPubMed
10.
Velayati A, Yu WH, Sidransky E. The role of glucocerebrosidase mutations in Parkinson disease and Lewy body disorders. Curr Neurol Neurosci Rep. 2010;10:190–8.CrossRefPubMedPubMedCentral
11.
Mata IF, Samii A, Schneer SH, Roberts JW, Griffith A, Leis BC, Schellenberg GD, Sidransky E, Bird TD, Leverenz JB, et al. Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch Neurol. 2008;65:379–82.CrossRefPubMedPubMedCentral
12.
Lwin A, Orvisky E, Goker-Alpan O, LaMarca ME, Sidransky E. Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab. 2004;81:70–3.CrossRefPubMed
13.
14.
Andres-Mateos E, Mejias R, Sasaki M, Li X, Lin BM, Biskup S, Zhang L, Banerjee R, Thomas B, Yang L, et al. Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). J Neurosci. 2009;29:15846–50.CrossRefPubMedPubMedCentral
15.
Thomas B, von Coelln R, Mandir AS, Trinkaus DB, Farah MH, Leong Lim K, Calingasan NY, Flint Beal M, Dawson VL, Dawson TM. MPTP and DSP-4 susceptibility of substantia nigra and locus coeruleus catecholaminergic neurons in mice is independent of parkin activity. Neurobiol Dis. 2007;26:312–22.CrossRefPubMedPubMedCentral
16.
Haque ME, Mount MP, Safarpour F, Abdel-Messih E, Callaghan S, Mazerolle C, Kitada T, Slack RS, Wallace V, Shen J, et al. Inactivation of Pink1 gene in vivo sensitizes dopamine-producing neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and can be rescued by autosomal recessive Parkinson disease genes, Parkin or DJ-1. J Biol Chem. 2012;287:23162–70.CrossRefPubMedPubMedCentral
17.
Noelker C, Lu L, Hollerhage M, Vulinovic F, Sturn A, Roscher R, Hoglinger GU, Hirsch EC, Oertel WH, Alvarez-Fischer D, Andreas H. Glucocerebrosidase deficiency and mitochondrial impairment in experimental Parkinson disease. J Neurol Sci. 2015;356:129–36.CrossRefPubMed
18.
Liu Y, Suzuki K, Reed JD, Grinberg A, Westphal H, Hoffmann A, Doring T, Sandhoff K, Proia RL. Mice with type 2 and 3 Gaucher disease point mutations generated by a single insertion mutagenesis procedure. Proc Natl Acad Sci U S A. 1998;95:2503–8.CrossRefPubMedPubMedCentral
19.
Ko HS, Lee Y, Shin JH, Karuppagounder SS, Gadad BS, Koleske AJ, Pletnikova O, Troncoso JC, Dawson VL, Dawson TM. Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function. Proc Natl Acad Sci U S A. 2010;107:16691–6.CrossRefPubMedPubMedCentral
20.
Karuppagounder SS, Brahmachari S, Lee Y, Dawson VL, Dawson TM, Ko HS. The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson's disease. Sci Rep. 2014;4:4874.CrossRefPubMedPubMedCentral
21.
Ko HS, Bailey R, Smith WW, Liu Z, Shin JH, Lee YI, Zhang YJ, Jiang H, Ross CA, Moore DJ, et al. CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity. Proc Natl Acad Sci U S A. 2009;106:2897–902.CrossRefPubMedPubMedCentral
22.
23.
Stevens DA, Lee Y, Kang HC, Lee BD, Lee YI, Bower A, Jiang H, Kang SU, Andrabi SA, Dawson VL, et al. Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration. Proc Natl Acad Sci U S A. 2015;112:11696–701.CrossRefPubMedPubMedCentral
24.
Choi S, Kim D, Kam TI, Yun S, Kim S, Park H, Hwang H, Pletnikova O, Troncoso JC, Dawson VL, et al. Lysosomal enzyme Glucocerebrosidase protects against Abeta1-42 Oligomer-induced neurotoxicity. PLoS One. 2015;10:e0143854.CrossRefPubMedPubMedCentral
25.
Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, Sidransky E, Grabowski GA, Krainc D. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011;146:37–52.CrossRefPubMedPubMedCentral
26.
Morgan AJ, Davis LC, Galione A. Imaging approaches to measuring lysosomal calcium. Methods Cell Biol. 2015;126:159–95.CrossRefPubMed
27.
Song LK, Ma KL, Yuan YH, Mu Z, Song XY, Niu F, Han N, Chen NH. Targeted Overexpression of α-Synuclein by rAAV2/1 vectors induces progressive Nigrostriatal degeneration and increases vulnerability to MPTP in mouse. PLoS One. 2015;10:e0131281.CrossRefPubMedPubMedCentral
28.
Tesseur I, Nguyen A, Chang B, Li L, Woodling NS, Wyss-Coray T, Luo J. Deficiency in neuronal TGF-β signaling leads to nigrostriatal degeneration and activation of TGF-β signaling protects against MPTP neurotoxicity in mice. J Neurosci. 2017;37:4584–92.CrossRefPubMedPubMedCentral
29.
Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, Ge P, Umanah GE, Brahmachari S, Shin JH, et al: Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science. 2016;353(6307):1513.
30.
Migdalska-Richards A, Daly L, Bezard E, Schapira AH. Ambroxol effects in glucocerebrosidase and alpha-synuclein transgenic mice. Ann Neurol. 2016;80:766–75.CrossRefPubMedPubMedCentral
31.
Clark LN, Kartsaklis LA, Wolf Gilbert R, Dorado B, Ross BM, Kisselev S, Verbitsky M, Mejia-Santana H, Cote LJ, Andrews H, et al. Association of glucocerebrosidase mutations with dementia with lewy bodies. Arch Neurol. 2009;66:578–83.CrossRefPubMedPubMedCentral
32.
Nishioka K, Ross OA, Vilarino-Guell C, Cobb SA, Kachergus JM, Mann DM, Snowden J, Richardson AM, Neary D, Robinson CA, et al. Glucocerebrosidase mutations in diffuse Lewy body disease. Parkinsonism Relat Disord. 2011;17:55–7.CrossRefPubMedPubMedCentral
33.
Shin JH, Ko HS, Kang H, Lee Y, Lee YI, Pletinkova O, Troconso JC, Dawson VL, Dawson TM. PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson’s disease. Cell. 2011;144:689–702.CrossRefPubMedPubMedCentral
34.
Lee Y, Karuppagounder SS, Shin JH, Lee YI, Ko HS, Swing D, Jiang H, Kang SU, Lee BD, Kang HC, et al. Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss. Nat Neurosci. 2013;16:1392–400.CrossRefPubMedPubMedCentral
35.
Burguillos MA, Deierborg T, Kavanagh E, Persson A, Hajji N, Garcia-Quintanilla A, Cano J, Brundin P, Englund E, Venero JL, Joseph B. Caspase signalling controls microglia activation and neurotoxicity. Nature. 2011;472:319–24.CrossRefPubMed
36.
Heffron DS, Landreth GE, Samuels IS, Mandell JW. Brain-specific deletion of extracellular signal-regulated kinase 2 mitogen-activated protein kinase leads to aberrant cortical collagen deposition. Am J Pathol. 2009;175:2586–99.CrossRefPubMedPubMedCentral
37.
Fishbein I, Kuo YM, Giasson BI, Nussbaum RL. Augmentation of phenotype in a transgenic Parkinson mouse heterozygous for a Gaucher mutation. Brain. 2014;137:3235–47.CrossRefPubMedPubMedCentral
38.
Thomas B, Mandir AS, West N, Liu Y, Andrabi SA, Stirling W, Dawson VL, Dawson TM, Lee MK. Resistance to MPTP-neurotoxicity in alpha-synuclein knockout mice is complemented by human alpha-synuclein and associated with increased β-synuclein and Akt activation. PLoS One. 2011;6:e16706.CrossRefPubMedPubMedCentral
39.
Dauer W, Kholodilov N, Vila M, Trillat AC, Goodchild R, Larsen KE, Staal R, Tieu K, Schmitz Y, Yuan CA, et al. Resistance of α-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci U S A. 2002;99:14524–9.CrossRefPubMedPubMedCentral
40.
Nicklas WJ, Youngster SK, Kindt MV, Heikkila RE. MPTP, MPP+ and mitochondrial function. Life Sci. 1987;40:721–9.CrossRefPubMed
41.
Schapira AH, Hartley A, Cleeter MW, Cooper JM. Free radicals and mitochondrial dysfunction in Parkinson's disease. Biochem Soc Trans. 1993;21:367–70.CrossRefPubMed
42.
Dawson TM, Dawson VL. Mitochondrial mechanisms of neuronal cell death: potential therapeutics. Annu Rev Pharmacol Toxicol. 2017;57:437–54.CrossRefPubMed
43.
Dawson TM, Dawson VL. Molecular pathways of neurodegeneration in Parkinson’s disease. Science. 2003;302:819–22.CrossRefPubMed
44.
Osellame LD, Rahim AA, Hargreaves IP, Gegg ME, Richard-Londt A, Brandner S, Waddington SN, Schapira AH, Duchen MR. Mitochondria and quality control defects in a mouse model of Gaucher disease--links to Parkinson’s disease. Cell Metab. 2013;17:941–53.CrossRefPubMedPubMedCentral
45.
Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. 2008;183:795–803.CrossRefPubMedPubMedCentral
46.
Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 2010;8:e1000298.CrossRefPubMedPubMedCentral
47.
48.
49.
Du TT, Wang L, Duan CL, Lu LL, Zhang JL, Gao G, Qiu XB, Wang XM, Yang H. GBA deficiency promotes SNCA/α-synuclein accumulation through autophagic inhibition by inactivated PPP2A. Autophagy. 2015;11:1803–20.CrossRefPubMedPubMedCentral
50.
Sardi SP, Singh P, Cheng SH, Shihabuddin LS, Schlossmacher MG. Mutant GBA1 expression and synucleinopathy risk: first insights from cellular and mouse models. Neurodegener Dis. 2012;10:195–202.CrossRefPubMed
51.
Swan M, Saunders-Pullman R. The association between ss-glucocerebrosidase mutations and parkinsonism. Curr Neurol Neurosci Rep. 2013;13:368.CrossRefPubMed
52.
Fornai F, Schluter OM, Lenzi P, Gesi M, Ruffoli R, Ferrucci M, Lazzeri G, Busceti CL, Pontarelli F, Battaglia G, et al. Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc Natl Acad Sci U S A. 2005;102:3413–8.CrossRefPubMedPubMedCentral
53.
Colla E, Coune P, Liu Y, Pletnikova O, Troncoso JC, Iwatsubo T, Schneider BL, Lee MK. Endoplasmic reticulum stress is important for the manifestations of α-synucleinopathy in vivo. J Neurosci. 2012;32:3306–20.CrossRefPubMedPubMedCentral
54.
Ong DS, Mu TW, Palmer AE, Kelly JW. Endoplasmic reticulum Ca2+ increases enhance mutant glucocerebrosidase proteostasis. Nat Chem Biol. 2010;6:424–32.CrossRefPubMedPubMedCentral
Metadata
Title
α-Synuclein accumulation and GBA deficiency due to L444P GBA mutation contributes to MPTP-induced parkinsonism
Authors
Seung Pil Yun
Donghoon Kim
Sangjune Kim
SangMin Kim
Senthilkumar S. Karuppagounder
Seung-Hwan Kwon
Saebom Lee
Tae-In Kam
Suhyun Lee
Sangwoo Ham
Jae Hong Park
Valina L. Dawson
Ted M. Dawson
Yunjong Lee
Han Seok Ko
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2018
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-017-0233-5

Other articles of this Issue 1/2018

Molecular Neurodegeneration 1/2018 Go to the issue

Research article

Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease

Commentary

Vibrational spectroscopy: a promising approach to discriminate neurodegenerative disorders

Review

Peripheral immune system in aging and Alzheimer’s disease

Research article

Cognitive impairment in metabolically-obese, normal-weight rats: identification of early biomarkers in peripheral blood mononuclear cells

Research article

A brain-penetrant triazolopyrimidine enhances microtubule-stability, reduces axonal dysfunction and decreases tau pathology in a mouse tauopathy model

Short report

Extracellular α-synuclein levels are regulated by neuronal activity