Gist als rijzende ster tegen de ziekte van Parkinson

Jens
Loncke

De ziekte van Parkinson

De ziekte van Parkinson is één van de meest voorkomende neurodegeneratieve aandoeningen met wereldwijd 7 tot 10 miljoen patiënten. Dit is hoogstwaarschijnlijk een onderschatting van het echte totaal, want artsen schrijven vaak symptomen van de ziekte van Parkinson toe aan normale verouderingsprocessen. De ziekte komt vooral voor bij ouderen en komt twee keer meer voor bij mannen dan bij vrouwen. De maandelijkse kost voor de gezondheidszorg ligt tussen de €2600 en €10 000 per patiënt in Europese landen. Deze kosten zullen nog fel stijgen, want door de vergrijzing van de bevolking zal de ziekte vaker voor komen. De belangrijkste symptomen zijn beven in rust, traagheid van bewegingen en spierstijfheid.  Wanneer deze symptomen ernstiger worden kan de arts symptomatische geneesmiddelen voorschrijven zoals levodopa of dopamine receptor agonisten. Deze behandelingen kunnen de patiënt echter niet genezen en zijn louter bedoeld om de symtomen draaglijker te maken. Bovendien verliezen deze behandelingen hun effectiviteit naarmate de ziekte erger wordt en komen er ook heel wat bijwerkingen bij kijken.

Het verlies van dopamine

De exacte mechanismes die bijdragen tot het ontwikkelen van de ziekte van Parkinson zijn niet bekend. Er wordt vermoed dat genetische factoren en omgevingsfactoren een rol spelen. Wat wel geweten is, is dat een groot deel van de dopamine producerende zenuwcellen in de hersenen sterven afsterft. Dopamine is een belangrijke neurotransmitter in het teweegbrengen van gecontroleerde spierbewegingen. Een groot deel van de cellen die afsterven bij het ontwikkelen van de ziekte van Parkinson zijn gepigmenteerd. Om die reden zijn hersenen van patiënten met de ziekte van Parkinson gemakkelijk te onderscheiden van die van gezonde patiënten. Onderstaande figuur toont de middenhersenen van een gezonde patiënt (links) en een patiënt met de ziekte van Parkinson (rechts).

In de overlevende zenuwcellen worden opeenstapelingen van eiwitten teruggevonden die ‘Lewy bodies’ worden genoemd.  Het grootste deel van die Lewy bodies bestaat uit het eiwit alfa-synucleïne en de interactiepartner synphilin-1. De exacte functies van deze eiwitten zijn niet gekend. Er wordt vermoed dat post-translationele modificaties, zoals ubiquitinatie, een invloed zouden kunnen hebben op het samenklonteren en de toxiciteit van deze eiwitten.

image-20190727111626-1

http://maplecarephysiotherapy.com/services/parkinsons-disease/

Transversale sectie van normale middenhersenen (links) en middenhersenen van een patiënt met de ziekte van Parkinson (rechts)

Gist als model voor de ziekte van Parkinson

In dit project worden deze eiwitten onderzocht in bakkersgist, door gebruik te maken van zogenaamde gehumaniseerde gistmodellen voor de Ziekte van Parkinson. Dit is mogelijk, omdat veel cellulaire processen in gist goed lijken op die in menselijke cellen. Alfa-synucleïne en synphilin-1 kunnen we tot expressie brengen in gist door gebruik te maken van een plasmide. Net zoals in menselijke zenuwcellen klonteren alfa-synucleïne en synphilin-1 ook samen in gistcellen. Een voorbeeld van het samenklonteren van alfa-synucleïne in een gistcel wordt hieronder getoond.

image 56

Fluorescente microscopieopname van een gistcel met samengeklonterd alfa-synucleïne. 

In deze studie onderzochten we de invloed van ubiquitinatie op de samenklontering en toxiciteit van alfa-synucleïne en synphilin-1 in gehumaniseerde gistmodellen. We gebruikten verschillende mutanten met verwijderde genen die belangrijk zijn in het ubiquitinatiesysteem van de cel. Onze resultaten suggereren dat een verlaagde vrije ubiquitine voorraad in de cel het samenklonteren van alfa-synucleïne in grotere, beschermende eiwitklonters zou kunnen bevorderen. Voor synphilin-1 was dit niet het geval. Verdere resultaten suggereerden dat dit initiële voordeel verdwijnt naarmate cellen ouder worden. Onze resultaten lijken een belangrijke rol toe te schrijven aan ubiquitinatie in het verwerken van alfa-synucleïne in de cel. Verder onderzoek zal echter noodzakelijk zijn om meer uitsluitsel te kunnen geven en de exacte mechanismen van de verwerking van alfa-synucleïne en synphilin-1 bloot te leggen. Het begrijpen van deze mechanismen kan er voor zorgen dat meer bekend wordt over hoe de ziekte van Parkinson ontwikkelt. Op die manier zou het in de toekomst mogelijk kunnen zijn om een genezende behandeling te ontwikkelen voor de ziekte van Parkinson. Een dergelijke behandeling zou de kosten voor de maatschappij behoorlijk kunnen drukken en veel lijden kunnen voorkomen.

Bibliografie

[1] A Elbaz et al. Epidemiology of Parkinson's disease. Revue Neurologique, 172(1):14{26, 2016. ISSN

0035-3787.

[2] Tamara Pringsheim et al. The prevalence of Parkinson's disease: A systematic review and metaanalysis.

Movement Disorders, 29(13):1583{1590, 2014.

[3] James Parkinson. An essay on the shaking palsy. Whittengham, London, reprint. edition, 1817.

[4] J A Obeso et al. Past, present, and future of Parkinson's disease: A special essay on the 200th

Anniversary of the Shaking Palsy. Movement Disorders, 32(9):1264{1310, 2017. ISSN 0885-3185.

[5] Anthony E Lang. A critical appraisal of the premotor symptoms of Parkinson's disease: potential

usefulness in early diagnosis and design of neuroprotective trials. Movement disorders : ocial

journal of the Movement Disorder Society, 26(5), 2011. ISSN 1531-8257.

[6] Fatemeh N Emamzadeh and Andrei Surguchov. Parkinson's Disease: Biomarkers, Treatment, and

Risk Factors. Frontiers in Neuroscience, 12:612, 2018. ISSN 1662-453X.

[7] Ji Hyun Ko and Antonio P Strafella. Dopaminergic neurotransmission in the human brain: New

lessons from perturbation and imaging. The Neuroscientist, 18(2):149{168, 2012. ISSN 1073-8584.

[8] M H Polymeropoulos et al. Mutation in the alpha-synuclein gene identi ed in families with Parkinson's

disease. Science, 276(5321):2045{2047, 1997. ISSN 00368075.

[9] Javier Simon-Sanchez et al. Genome-wide association study reveals genetic risk underlying Parkinson's

disease. Nature, pages S24|-S28B, 2010. ISSN 00280836.

[10] Maria Grazia Spillantini et al. alpha-Synuclein in Lewy bodies. Nature, 388(6645), 1997. ISSN

0028-0836.

[11] Simone Engelender et al. Synphilin-1 associates with alpha-synuclein and promotes the formation

of cytosolic inclusions. Nature Genetics, 22(1), 1999. ISSN 1061-4036.

[12] Jose Obeso et al. Missing pieces in the Parkinson's disease puzzle. Nature, pages S31|-S39, 2010.

ISSN 00280836.

[13] Tohru Kitada et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.

Nature, 392(6676), 1998. ISSN 0028-0836.

[14] Vincenzo Bonifati et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset

parkinsonism. Science (New York, N.Y.), 299(5604), 2003. ISSN 1095-9203.

[15] Enza Maria Valente et al. PINK1 mutations are associated with sporadic early-onset parkinsonism.

Annals of Neurology, 56(3):336{341, 2004. ISSN 0364-5134.

[16] Alexander Zimprich et al. Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with

Pleomorphic Pathology. Neuron, 44(4):601{607, 2004. ISSN 0896-6273.

[17] Vanesa Bellou et al. Environmental risk factors and Parkinson's disease: An umbrella review of

meta-analyses. Parkinsonism and Related Disorders, 23(C):1{9, 2016. ISSN 1353-8020.

[18] Marvin M Goldenberg. Medical management of Parkinson's disease. P and T, 33(10):590{606,

2008. ISSN 10521372.

[19] V Franssens et al. The Bene ts of Humanized Yeast Models to Study Parkinson's Disease. Oxidative

Medicine and Cellular Longevity, 2013, 2013. ISSN 1942-0900.

[20] Johnathan Labbadia and Richard I Morimoto. The Biology of Proteostasis in Aging and Disease.

Annual Review of Biochemistry, 84(1):435{464, 2015. ISSN 0066-4154.

[21] Harvey Lodish, Arnold Berk, and Paul Matsudaira. Molecular Cell Biology. Freeman, New York,

5th ed., 2nd print. edition, 2004. ISBN 0716743663.

[22] F Ulrich Hartl. Cellular Homeostasis and Aging. Annual Review of Biochemistry, 85(1):1{4, 2016.

ISSN 0066-4154.

[23] Chang Chung, Hyosang Lee, and Sung Lee. Mechanisms of protein toxicity in neurodegenerative

diseases. Cellular and Molecular Life Sciences, 75(17):3159{3180, 2018. ISSN 1420-682X.

[24] Bryan Chen et al. Cellular strategies of protein quality control. Cold Spring Harbor perspectives

in biology, 3(8), 2011. ISSN 1943-0264.

[25] Jens Tyedmers, Axel Mogk, and Bernd Bukau. Cellular strategies for controlling protein aggregation.

Nature Reviews Molecular Cell Biology, 11(11), 2010. ISSN 1471-0072.

[26] A Ciechanover and Y T Kwon. Protein quality control by molecular chaperones in neurodegeneration.

Frontiers in Neuroscience, 11, 2017. ISSN 16624548.

[27] Alice I Bartlett and Sheena E Radford. An expanding arsenal of experimental methods yields an

explosion of insights into protein folding mechanisms. Nature Structural & Molecular Biology, 16

(6), 2009. ISSN 1545-9993.

[28] Veronique Albanese et al. Systems Analyses Reveal Two Chaperone Networks with Distinct Functions

in Eukaryotic Cells. Cell, 124(1):75{88, 2006. ISSN 0092-8674.

[29] Martin Haslbeck et al. Some like it hot: the structure and function of small heat-shock proteins.

Nature Structural & Molecular Biology, 12(10), 2005. ISSN 1545-9993.

[30] F. Ulrich Hartl, Andreas Bracher, and Manajit Hayer-Hartl. Molecular chaperones in protein

folding and proteostasis. Nature, 475(7356), 2011. ISSN 0028-0836.

[31] Julia C. Ranford, Anthony R.M. Coates, and Brian Henderson. Chaperonins are cell-signalling

proteins: the unfolding biology of molecular chaperones. Expert Reviews in Molecular Medicine, 2

(8):1{17, 2000. ISSN 1462-3994.

[32] Dick D. Mosser, Sylvia Ho, and John R. Glover. Saccharomyces cerevisiae hsp 104 enhances

the chaperone capacity of human cells and inhibits heat stress-induced proapoptotic signaling.

Biochemistry, 43(25), 2004. ISSN 0006-2960.

[33] S.-Y. Wu et al. The anaphase-promoting complex works together with the SCF complex for proteolysis

of the S-phase cyclin Clb6 during the transition from G1 to S phase. Fungal Genetics and

Biology, 91:6{19, 2016. ISSN 10871845.

[34] Ivan Dikic. Proteasomal and Autophagic Degradation Systems. Annual Review of Biochemistry,

86:193{224, 2017. ISSN 0066-4154.

[35] Lauren Budenholzer et al. Proteasome Structure and Assembly. Journal of Molecular Biology, 429

(22):3500{3524, 2017. ISSN 0022-2836.

[36] A Hershko and A Ciechanover. The ubiquitin system for protein degradation. Annual Review of

Biochemistry, 61(1):761{807, 1992. ISSN 0066-4154.

[37] A L Haas et al. Ubiquitin-activating enzyme. Mechanism and role in protein-ubiquitin conjugation.

Journal of Biological Chemistry, 257(5):2543{2548, 1982. ISSN 00219258.

[38] M Rechsteiner. Ubiquitin-mediated pathways for intracellular proteolysis. Annual Review of Cell

Biology, 3(1):1{30, 1987. ISSN 0743-4634.

[39] Alexander Varshavsky. The Ubiquitin System, Autophagy, and Regulated Protein Degradation.

Annual Review of Biochemistry, 86:123{128, 2017. ISSN 0066-4154.

[40] D Komander. The emerging complexity of protein ubiquitination. Biochemical Society Transac-

tions, 37(Pt 5):937{953, 2009. ISSN 0300-5127.

[41] L Buetow and Dt Huang. Structural insights into the catalysis and regulation of E3 ubiquitin

ligases. Nature Reviews Molecular Cell Biology, 17(10):626{642, 2016. ISSN 1471-0072.

[42] Rj Deshaies and C A P Joazeiro. RING Domain E3 Ubiquitin Ligases. Annual Review Of Bio-

chemistry, 78(1):399{434, 2009. ISSN 0066-4154.

[43] Yves Leestemaker and Huib Ovaa. Tools to investigate the ubiquitin proteasome system. Drug

Discovery Today: Technologies, 26:25{31, 2017. ISSN 1740-6749.

[44] Choi S. Encyclopedia of Signaling Molecules. Springer International Publishing, Cham, 2018. ISBN

9783319671987.

[45] Kaisa Haglund et al. Multiple monoubiquitination of RTKs is sucient for their endocytosis and

degradation. Nature Cell Biology, 5(5), 2003. ISSN 1465-7392.

[46] Randy Suryadinata et al. Mechanisms of generating polyubiquitin chains of di erent topology. Cells,

3(3):674{689, 2014. ISSN 2073-4409. URL http://search.proquest.com/docview/1682214136/.

[47] Mark Windheim, Mark Peggie, and Philip Cohen. Two di erent classes of E2 ubiquitin-conjugating

enzymes are required for the mono-ubiquitination of proteins and elongation by polyubiquitin chains

with a speci c topology. The Biochemical journal, 409(3), 2008. ISSN 1470-8728.

[48] Kaisa Haglund and Ivan Dikic. The role of ubiquitylation in receptor endocytosis and endosomal

sorting. Journal of cell science, 125(Pt 2), 2012. ISSN 1477-9137.

[49] Zoi Alexopoulou et al. Deubiquitinase Usp8 regulates [alpha]-synuclein clearance and modi es

its toxicity in Lewy body disease.(PNAS PLUS: NEUROSCIENCE)(Report). Proceedings of the

National Academy of Sciences of the United States, 113(32), 2016. ISSN 0027-8424.

[50] Francisca E Reyes-Turcu, Karen H Ventii, and Keith D Wilkinson. Regulation and cellular roles

of ubiquitin-speci c deubiquitinating enzymes. Annual review of biochemistry, 78(1), 2009. ISSN

1545-4509.

[51] Michael Groll et al. A gated channel into the proteasome core particle. Nature Structural Biology,

7:1062, nov 2000.

[52] Tetsuro Yoshimura et al. Molecular Characterization of the "26S" Proteasome Complex from Rat

Liver. Journal of Structural Biology, 111(3):200{211, 1993. ISSN 1047-8477.

[53] Marc Wehmer et al. Structural insights into the functional cycle of the ATPase module of the 26S

proteasome. Proceedings of the National Academy of Sciences of the United States of America, 114

(6), 2017. ISSN 1091-6490.

[54] Suzanne Elsasser et al. Proteasome subunit Rpn1 binds ubiquitin-like protein domains. Nature

Cell Biology, 4(9), 2002. ISSN 1465-7392.

[55] Koraljka Husnjak et al. Proteasome subunit Rpn13 is a novel ubiquitin receptor. Nature, 453

(7194), 2008. ISSN 0028-0836.

[56] Evan J Worden, Chris Padovani, and Andreas Martin. Structure of the Rpn11-Rpn8 dimer reveals

mechanisms of substrate deubiquitination during proteasomal degradation.(Report). Nature

Structural and Molecular Biology, 21(3), 2014. ISSN 1545-9993.

[57] Q Deveraux et al. A 26 S protease subunit that binds ubiquitin conjugates. The Journal of biological

chemistry, 269(10), 1994. ISSN 0021-9258.

[58] Ub Pandey et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy

and the UPS. Nature, 447(7146):859{863, 2007. ISSN 0028-0836.

[59] Palaniyandi Ravanan, Ida Florance Srikumar, and Priti Talwar. Autophagy: The spotlight for

cellular stress responses. Life Sciences, 188:53{67, 2017. ISSN 0024-3205.

[60] Wen-wen Li, Jian Li, and Jin-ku Bao. Microautophagy: lesser-known self-eating. Cellular and

Molecular Life Sciences, 69(7):1125{1136, 2012. ISSN 1420-682X.

[61] Hui-Ling Chiang, Stanley Terlecky, Charles Plant, and J Dice. A role for a 70-kilodaton heat

shock protein in lysosomal degradation of intracellular proteins. Science, 246(4928), 1989. ISSN

00368075. URL http://search.proquest.com/docview/213536846/.

[62] Susmita Kaushik and Ana Maria Cuervo. Chaperone-mediated autophagy: a unique way to enter

the lysosome world. Trends in Cell Biology, 22(8):407{417, 2012. ISSN 0962-8924.

[63] V Nikoletopoulou, M-E Papandreou, and N Tavernarakis. Autophagy in the physiology and pathology

of the central nervous system. Cell Death and Di erentiation, 22(3), 2014. ISSN 1350-9047.

[64] Jean-Claude Farre and Suresh Subramani. Mechanistic insights into selective autophagy pathways:

lessons from yeast. Nature Reviews Molecular Cell Biology, 17(9), 2016. ISSN 1471-0072.

[65] Yuchen Feng, Ding He, Zhiyuan Yao, and Daniel J Klionsky. The machinery of macroautophagy.

Cell Research, 24(1), 2013. ISSN 1001-0602.

[66] Ingo Amm, Thomas Sommer, and Dieter H Wolf. Protein quality control and elimination of protein

waste: The role of the ubiquitin{proteasome system. BBA - Molecular Cell Research, 1843(1):182{

196, 2014. ISSN 0167-4889.

[67] Kara L. Schneider, Thomas Nystrom, and Per O. Widlund. Studying spatial protein quality control,

proteopathies, and aging using di erent model misfolding proteins in s. cerevisiae. Frontiers in

Molecular Neuroscience, 11, 2018. ISSN Frontiers in Molecular Neuroscience.

[68] Stephanie B M Miller, Axel Mogk, and Bernd Bukau. Spatially Organized Aggregation of Misfolded

Proteins as Cellular Stress Defense Strategy. Journal of Molecular Biology, 427(7):1564{1574, 2015.

ISSN 0022-2836.

[69] Heidi Olzscha et al. Amyloid-like Aggregates Sequester Numerous Metastable Proteins with Essential

Cellular Functions. Cell, 144(1):67{78, 2011. ISSN 0092-8674.

[70] Daniel Kaganovich, Ron Kopito, and Judith Frydman. Misfolded proteins partition between two

distinct quality control compartments. Nature, 454(7208), 2008. ISSN 0028-0836.

[71] Sandra Malmgren Hill, Sarah Hanzen, and Thomas Nystrom. Restricted access: spatial sequestration

of damaged proteins during stress and aging. EMBO reports, 18(3):377{391, 2017. ISSN

1469-221X.

[72] Stephanie Bm Miller et al. Compartment-speci c aggregases direct distinct nuclear and cytoplasmic

aggregate deposition. EMBO Journal, 34(6):778{797, 2015. ISSN 0261-4189.

[73] Jennifer A Johnston, Cristina L Ward, and Ron R Kopito. Aggresomes: A Cellular Response to

Misfolded Proteins. The Journal of Cell Biology, 143(7):1883{1898, 1998. ISSN 0021-9525.

[74] Ayala Shiber et al. Ubiquitin conjugation triggers misfolded protein sequestration into quality

control foci when Hsp70 chaperone levels are limiting. Molecular biology of the cell, 24(13), 2013.

ISSN 1939-4586.

[75] Sebastian Specht et al. Hsp42 is required for sequestration of protein aggregates into deposition sites

in Saccharomyces cerevisiae. The Journal of Cell Biology, 195(4):617{629, 2011. ISSN 0021-9525.

[76] Jurre Hageman et al. Comparison of intra-organellar chaperone capacity for dealing with stressinduced

protein unfolding. The Journal of Biological Chemistry, 282(47):34334{34345, 2007. ISSN

0021-9258.

[77] Jens Tyedmers et al. Prion induction involves an ancient system for the sequestration of aggregated

proteins and heritable changes in prion fragmentation. Proceedings of the National Academy of

Sciences, 107(19), 2010. ISSN 0027-8424.

[78] Mick F Tuite and Tricia R Serio. The prion hypothesis: from biological anomaly to basic regulatory

mechanism. Nature Reviews Molecular Cell Biology, 11(12), 2010. ISSN 1471-0072.

[79] Stephanie Rothe, Abaya Prakash, and Jens Tyedmers. The Insoluble Protein Deposit (IPOD) in

Yeast. Frontiers in molecular neuroscience, 11:237, jul 2018. ISSN 1662-5099.

[80] Sren Vedel, Harry Nunns, Andrej Kosmrlj, Szabolcs Semsey, and Ala Trusina. Asymmetric damage

segregation constitutes an emergent population-level stress response. Cell Systems, 3(2):187{198,

2016. ISSN 2405-4712.

[81] Thomas Nystrom and Beidong Liu. Protein quality control in time and space { links to cellular

aging. FEMS Yeast Research, 14(1):40{48, 2014. ISSN 1567-1356.

[82] Nika Erjavec et al. Accelerated aging and failure to segregate damaged proteins in Sir2 mutants

can be suppressed by overproducing the protein aggregation-remodeling factor Hsp104p. Genes &

Development, 21(19), 2007. ISSN 0890-9369.

[83] Beidong Liu et al. The Polarisome Is Required for Segregation and Retrograde Transport of Protein

Aggregates. Cell, 140(2):257{267, 2010. ISSN 0092-8674.

[84] Ian G Macara and Stavroula Mili. Polarity and Di erential Inheritance|Universal Attributes of

Life? Cell, 135(5):801{812, 2008. ISSN 0092-8674.

[85] F Ulrich Hartl. Protein Misfolding Diseases. Annual Review of Biochemistry, 86:21{26, 2017. ISSN

0066-4154.

[86] Anna Villar-Pique, Tomas Lopes Da Fonseca, and Tiago Fleming Outeiro. Structure, function and

toxicity of alpha-synuclein: the Bermuda triangle in synucleinopathies. Journal of Neurochemistry,

139(S1):240{255, 2016. ISSN 0022-3042.

[87] Katherina Vamvaca, Michael J Volles, and Peter T Lansbury. The First N-terminal Amino Acids

of -Synuclein Are Essential for -Helical Structure Formation In Vitro and Membrane Binding in

Yeast. Journal of Molecular Biology, 389(2):413{424, 2009. ISSN 0022-2836.

[88] Dhiman Ghosh et al. Structure based aggregation studies reveal the presence of helix-rich intermediate

during -Synuclein aggregation. Scienti c Reports, 5(1), 2015. ISSN 2045-2322.

[89] G S Withers et al. Delayed localization of synel n (synuclein, NACP) to presynaptic terminals

in cultured rat hippocampal neurons. Brain research. Developmental brain research, 99(1), 1997.

ISSN 0165-3806.

[90] Seung-Jae Lee, Hyesung Jeon, and Konstantin V Kandror. Alpha-synuclein is localized in a subpopulation

of rat brain synaptic vesicles. Acta neurobiologiae experimentalis, 68(4):509{515, 2008.

ISSN 0065-1400.

[91] Misun Ahn et al. Chaperone-like activities of -synuclein: -Synuclein assists enzyme activities of

esterases. Biochemical and Biophysical Research Communications, 346(4):1142{1149, 2006. ISSN

0006-291X.

[92] Anoop Rawat, Ralf Langen, and Jobin Varkey. Membranes as modulators of amyloid protein

misfolding and target of toxicity. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1860(9):

1863{1875, 2018. ISSN 0005-2736.

[93] V N Uversky et al. Biophysical properties of the synucleins and their propensities to brillate:

Inhibition of -synuclein assembly by - and -synucleins. Journal of Biological Chemistry, 277

(14):11970{11978, 2002. ISSN 00219258.

[94] W.S. Davidson, A. Jonas, D.F. Clayton, and J.M. George. Stabilization of alpha-synuclein secondary

structure upon binding to synthetic membranes. Journal of Biological Chemistry, 273(16):

9443{9449, 1998. ISSN 00219258.

[95] Muthu Ramakrishnan, Poul H Jensen, and Derek Marsh. Alpha-synuclein association with phosphatidylglycerol

probed by lipid spin labels. Biochemistry, 42(44), 2003. ISSN 0006-2960.

[96] Marie-Francoise Chesselet. In vivo alpha-synuclein overexpression in rodents: A useful model of

parkinson's disease? Experimental Neurology, 209(1):22{27, 2008. ISSN 0014-4886.

[97] M Tanaka et al. Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective. Journal

Of Biological Chemistry, 279(6):4625{4631, 2004. ISSN 0021-9258.

[98] C Warren Olanow et al. Lewy-body formation is an aggresome-related process: a hypothesis. The

Lancet. Neurology, 3(8):496{503, 2004. ISSN 1474-4422.

[99] Michael J Volles and Peter T Lansbury. Vesicle permeabilization by proto brillar alpha-synuclein

is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism. Biochem-

istry, 41(14):4595{4602, 2002. ISSN 0006-2960.

[100] Leo Chen et al. Oligomeric alpha-synuclein inhibits tubulin polymerization. Biochemical and

biophysical research communications, 356(3):548{553, 2007. ISSN 0006-291X.

[101] Yaping Chu et al. Alterations in axonal transport motor proteins in sporadic and experimental

Parkinson's disease. Brain, 135(7):2058{2073, 2012. ISSN 0006-8950.

[102] Yaping Chu et al. Alterations in lysosomal and proteasomal markers in Parkinson's disease: Relationship

to alpha-synuclein inclusions. Neurobiology of Disease, 35(3):385{398, 2009. ISSN 0969-

9961.

[103] S A Tanik et al. Lewy Body-like alpha-Synuclein Aggregates Resist Degradation and Impair

Macroautophagy. Journal Of Biological Chemistry, 288(21):15194{15210, 2013. ISSN 0021-9258.

[104] Lisa Zondler et al. Proteasome impairment by alpha-synuclein. PLOS ONE, 12(9), 2017. ISSN

PLOS ONE.

[105] Edward Pajarillo et al. BBA - Molecular Basis of Disease The role of posttranslational modi

cations of  -synuclein and LRRK2 in Parkinson ' s disease : Potential contributions of environmental

factors. BBA - Molecular Basis of Disease, (November):0{1, 2018. ISSN 0925-4439.

[106] Hideo Fujiwara et al. -Synuclein is phosphorylated in synucleinopathy lesions. Nature Cell Biology,

4:160, jan 2002.

[107] Martial K Mbefo et al. Phosphorylation of synucleins by members of the Polo-like kinase family.

The Journal of biological chemistry, 285(4), 2010. ISSN 1083-351X.

[108] A L McCormack, S K Mak, and D A Di Monte. Increased -synuclein phosphorylation and nitration

in the aging primate substantia nigra. Cell Death &Amp; Disease, 3:e315, may 2012.

[109] Kang-Woo Lee et al. Enhanced Phosphatase Activity Attenuates -Synucleinopathy in a Mouse

Model. Journal of Neuroscience, 31(19):6963{6971, 2011. ISSN 0270-6474.

[110] M Hasegawa et al. Phosphorylated -synuclein is ubiquitinated in -synucleinopathy lesions. Jour-

nal of Biological Chemistry, 277(50):49071{49076, 2002. ISSN 00219258.

[111] J P Anderson et al. Phosphorylation of Ser-129 is the dominant pathological modi cation of -

synuclein in familial and sporadic lewy body disease. Journal of Biological Chemistry, 281(40):

29739{29752, 2006. ISSN 00219258.

[112] Ruth Rott et al.  -Synuclein fate is determined by USP9X-regulated monoubiquitination. Pro-

ceedings of the National Academy of Sciences of the United States of America, 108(46):1{6, 2011.

[113] Avram Hershko and Aaron Ciechanover. THE UBIQUITIN SYSTEM. Annual Review of Biochem-

istry, 67(1):425{479, 1998.

[114] George K Tofaris et al. Ubiquitin ligase Nedd4 promotes -synuclein degradation by the endosomal{

lysosomal pathway. Proceedings of the National Academy of Sciences, 108(41), 2011. ISSN

0027-8424.

[115] S Swaminathan, A Y Amerik, and M Hochstrasser. The Doa4 deubiquitinating enzyme is required

for ubiquitin homeostasis in yeast. Molecular biology of the cell, 10(8), 1999. ISSN 1059-1524.

[116] Kefeng Lu, Ivan Psakhye, and Stefan Jentsch. Autophagic Clearance of PolyQ Proteins Mediated

by Ubiquitin-Atg8 Adaptors of the Conserved CUET Protein Family. Cell, 158(3):549{563, 2014.

ISSN 0092-8674.

[117] George K Tofaris, Robert Lay eld, and Maria Grazia Spillantini. -Synuclein metabolism and

aggregation is linked to ubiquitin-independent degradation by the proteasome. FEBS Letters, 509

(1):22{26, 2001. ISSN 0014-5793.

[118] Rejko Kruger. The role of synphilin-1 in synaptic function and protein degradation. Cell and

Tissue Research, 318(1):195{199, 2004. ISSN 0302-766X.

[119] Sabrina Buttner et al. Synphilin-1 Enhances -Synuclein Aggregation in Yeast and Contributes

to Cellular Stress and Cell Death in a Sir2-Dependent Manner. PLoS One, 5(10), 2010. ISSN

1932-6203.

[120] Frank P Marx et al. The proteasomal subunit s6 atpase is a novel synphilin-1 interacting protein{

implications for parkinson's disease. FASEB journal : ocial publication of the Federation of

American Societies for Experimental Biology, 21(8):1759{1767, 2007. ISSN 1530-6860.

[121] David Botstein and Steven A Chervitz. Yeast as a model organism.(similar proteins encoded in

yeasts and mammals). Science, 277(5330), 1997. ISSN 0036-8075.

[122] Shahin Mohammadi and o. Scope and limitations of yeast as a model organism for studying human

tissue-speci c pathways. BMC systems biology, 9(96), 2015. ISSN 1752-0509.

[123] Tiago Fleming Outeiro and Susan Lindquist. Yeast cells provide insight into alpha-synuclein biology

and pathobiology. Science (New York, N.Y.), 302(5651):1772{1775, 2003. ISSN 1095-9203.

[124] Qh Chen, J Thorpe, and Jn Keller. alpha-synuclein alters proteasome function, protein synthesis,

and stationary phase viability. Journal Of Biological Chemistry, 280(34):30009{30017, 2005. ISSN

0021-9258.

[125] Kevin Mcnaught St. P. et al. Proteasome inhibition causes nigral degeneration with inclusion bodies

in rats. Neuroreport, 13(11):1437{1441, 2002. ISSN 0959-4965.

[126] N Sharma et al. -synuclein budding yeast model: Toxicity enhanced by impaired proteasome and

oxidative stress. Journal of Molecular Neuroscience, 28(2):161{178, 2006. ISSN 08958696.

[127] D Petroi et al. Aggregate clearance of -synuclein in Saccharomyces cerevisiae depends more on

autophagosome and vacuole function than on the proteasome. Journal of Biological Chemistry, 287

(33):27567{27579, 2012. ISSN 00219258.

[128] Piotr Zabrocki et al. Characterization of alpha-synuclein aggregation and synergistic toxicity with

protein tau in yeast. FEBS Journal, 272(6):1386{1400, 2005. ISSN 1742-464X.

[129] V Franssens et al. Yeast unfolds the road map toward alpha-synuclein-induced cell death. Cell

Death and Di erentiation, 17(5), 2009. ISSN 1350-9047.

[130] Sabrina Buttner et al. Functional mitochondria are required for alpha-synuclein toxicity in aging

yeast. The Journal of biological chemistry, 283(12):7554{7560, 2008. ISSN 0021-9258.

[131] Catia S Ribeiro et al. Synphilin-1 is developmentally localized to synaptic terminals, and its association

with synaptic vesicles is modulated by alpha-synuclein. The Journal of biological chemistry,

277(26):23927{23933, 2002. ISSN 0021-9258.

[132] Feroz R Papa and Mark Hochstrasser. The yeast DOA4 gene encodes a deubiquitinating enzyme

related to a product of the human tre-2 oncogene. Nature, 366(6453), 1993. ISSN 0028-0836.

[133] A Y Amerik, J Nowak, S Swaminathan, and M Hochstrasser. The Doa4 deubiquitinating enzyme

is functionally linked to the vacuolar protein-sorting and endocytic pathways. Molecular biology of

the cell, 11(10):3365{3380, 2000. ISSN 1059-1524.

[134] Elina Nikko and Bruno Andre. Evidence for a Direct Role of the Doa4 Deubiquitinating Enzyme

in Protein Sorting into the MVB Pathway. Trac, 8(5):566{581, 2007. ISSN 1398-9219.

[135] Deutschbauer AM et al. Mechanisms of haploinsuciency revealed by genome-wide pro ling in

yeast. Genetics, 169(4):1915{1925, apr 2005. ISSN 0016-6731.

[136] Burtner CR et al. A genomic analysis of chronological longevity factors in budding yeast. Cell

cycle (Georgetown, Tex.), 10(9):1385{1396, may 2011. ISSN 1538-4101.

[137] ME Nickas and MP Ya e. Bro1, a novel gene that interacts with components of the pkc1p-mitogenactivated

protein kinase pathway in saccharomyces cerevisiae. Molecular and Cellular Biology, 16

(6), 1996. ISSN 0270-7306.

[138] Greg Odorizzi, David J Katzmann, et al. Bro1 is an endosome-associated protein that functions

in the mvb pathway in saccharomyces cerevisiae. Journal of cell science, 116(Pt 10), 2003. ISSN

0021-9533.

[139] Natalie Luhtala and Greg Odorizzi. Bro1 coordinates deubiquitination in the multivesicular body

pathway by recruiting doa4 to endosomes.(author abstract). The Journal of Cell Biology, 166(5),

2004. ISSN 0021-9525.

[140] Lydie Michaillat et al. Identi cation of genes a ecting vacuole membrane fragmentation in saccharomyces

cerevisiae. PLoS ONE, 8(2), 2013. ISSN PLoS ONE.

[141] Wenjie Xu et al. Multivesicular body-escrt components function in ph response regulation in

saccharomyces cerevisiae and candida albicans. Molecular Biology of the Cell, 15(12):5528{5537,

2004. ISSN 10591524.

[142] R Daniel Gietz. Yeast transformation by the LiAc/SS carrier DNA/PEG method. Methods in

molecular biology (Clifton, N.J.), 1205:1{12, 2014. ISSN 19406029.

[143] J Kapuscinski. DAPI: a DNA-speci c uorescent probe. Biotechnic & histochemistry : ocial

publication of the Biological Stain Commission, 70(5):220{233, sep 1995. ISSN 1052-0295 (Print).

[144] Dalibor Mijaljica, Mark Prescott, and Rodney J Devenish. A uorescence microscopy assay for

monitoring mitophagy in the yeast Saccharomyces cerevisiae. Journal of visualized experiments :

JoVE, (53), 2011. ISSN 1940-087X (Electronic).

[145] Zongtian Tong. Yeast Vacuole Staining with FM4-64. Bio-protocol, 1(1):e18, 2011. ISSN 2331-8325.

[146] Hitesh M Peshavariya, Gregory James Dusting, and Stavros Selemidis. Analysis of dihydroethidium

uorescence for the detection of intracellular and extracellular superoxide produced by NADPH

oxidase. Free Radical Research, 2007, Vol.41(6), p.699-712, 41(6):699{712, 2007. ISSN 1071-5762.

[147] Carlo Riccardi and Ildo Nicoletti. Analysis of apoptosis by propidium iodide staining and ow

cytometry. Nature Protocols, 1:1458, nov 2006.

[148] W. Herth and E. Schnepf. The uorochrome, calco uor white, binds oriented to structural polysaccharide

brils. Protoplasma, 105(1):129{133, Mar 1980. ISSN 1615-6102.

[149] Martina Balaz and Alf Mansson. Detection of small di erences in actomyosin function using actin

labeled with di erent phalloidin conjugates. Analytical Biochemistry, 338(2):224{236, 2005. ISSN

0003-2697.

[150] Anneliese M. Lengsfeld et al. Interaction of phalloidin with actin. Proceedings of the National

Academy of Sciences of the United States of America, 71(7), 1974. ISSN 0027-8424.

[151] Terunao Takahara and Tatsuya Maeda. Transient Sequestration of TORC1 into Stress Granules

during Heat Stress. Molecular Cell, 47(2):242{252, 2012. ISSN 1097-2765.

[152] Hucheng Zhang et al. Immunological characterization and veri cation of recombinant streptococcal

protein G. Molecular medicine reports, 12(4):6311{6315, 2015. ISSN 1791-3004.

[153] Julien Picot et al. Flow cytometry: retrospective, fundamentals and recent instrumentation. Cy-

totechnology, 64(2):109{130, mar 2012. ISSN 0920-9069.

[154] Johannes Schindelin, Ignacio Arganda-Carreras, Erwin Frise, Verena Kaynig, Mark Longair, Tobias

Pietzsch, Stephan Preibisch, Curtis Rueden, Stephan Saalfeld, Benjamin Schmid, Jean-Yves

Tinevez, Daniel James White, Volker Hartenstein, Kevin Eliceiri, Pavel Tomancak, and Albert

Cardona. Fiji: an open-source platform for biological-image analysis. Nature Methods, 9(7), 2012.

ISSN 1548-7091.

[155] R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical

Computing, Vienna, Austria, 2013.

[156] Russel V. Lenth. Least-squares means: The R package lsmeans. Journal of Statistical Software, 69

(1):1{33, 2016.

[157] Kathleen Sprou ske and Andreas Wagner. Growthcurver: an r package for obtaining interpretable

metrics from microbial growth curves.(report). BMC Bioinformatics, 17(149), 2016. ISSN 1471-

2105.

[158] J. A. Hartigan and M. A. Wong. A k-means clustering algorithm. Journal of the Royal Statistical

Society: Series C (Applied Statistics), 28(1):100{108, 1979. ISSN 0035-9254.

[159] Hadley Wickham. ggplot2: Elegant Graphics for Data Analysis. Springer-Verslag New York, 2016.

[160] Kirby N Swatek and David Komander. Ubiquitin modi cations. Cell Research, 26(4), 2016. ISSN

1001-0602.

[161] James B. Moseley and Bruce L Goode. The yeast actin cytoskeleton: from cellular function to

biochemical mechanism. Microbiology and Molecular Biology Reviews, 70(3), 2006. ISSN 1092-

2172.

[162] Jordi Doijen. Humanized yeast models to study aggregation of the parkinson's disease related

proteins alpha-synuclein and synphilin-1, 2015.

[163] Pj Mclean et al. alpha-synuclein-enhanced green uorescent protein fusion proteins form proteasome

sensitive inclusions in primary neurons. Neuroscience, 104(3):901{912, 2001. ISSN 0306-4522.

[164] Quinghua Chen, Qunxing Ding, and Je rey Keller. The stationary phase model of aging in yeast for

the study of oxidative stress and age-related neurodegeneration. Biogerontology, 6(1):1{13, 2005.

ISSN 1389-5729.

[165] Piotr Zabrocki et al. Phosphorylation, lipid raft interaction and trac of alpha-synuclein in a yeast

model for parkinson. BBA - Molecular Cell Research, 1783(10):1767{1780, 2008. ISSN 0167-4889.

[166] Lorraine V Kalia and Anthony E Lang. Parkinson's disease. Lancet (London, England), 386(9996):

896{912, 2015. ISSN 1474-547X.

[167] Theo Vos et al. Global, regional, and national incidence, prevalence, and years lived with disability

for 310 diseases and injuries, 1990{2015: a systematic analysis for the global burden of disease

study 2015. The Lancet, 388(10053):1545{1602, 2016. ISSN 01406736.

[168] R. Dorsey et al. Projected number of people with parkinson disease in the most populous nations,

2005 through 2030. Neurology, 68(5):384{386, 2007. ISSN 0028-3878.

[169] Fredericks et al. Parkinson's disease and parkinson's disease psychosis: a perspective on the challenges,

treatments, and economic burden. The American journal of managed care, 23(5 Suppl):

S83{S92, 2017. ISSN 1936-2692.

[170] MC Bennett, Jf Bishop, Y Leng, Pb Chock, Tn Chase, and MM Mouradian. Degradation of alphasynuclein

by proteasome. Journal Of Biological Chemistry, 274(48):33855{33858, 1999. ISSN

0021-9258.

[171] Gernot Fruhmann et al. The impact of escrt on abeta induced membrane lesions in a yeast model

for alzheimer's disease. Frontiers in molecular neuroscience, 11, 2018. ISSN 1662-5099.

[172] Qunxing Ding and Je rey N. Keller. Proteasome inhibition in oxidative stress neurotoxicity: implications

for heat shock proteins. Journal of Neurochemistry, 77(4):1010{1017, 2001. ISSN 0022-3042.

[173] E Swinnen, S Buttner, Tf Outeiro, MC Galas, F Madeo, J Winderickx, and V Franssens. Aggresome

formation and segregation of inclusions in uence toxicity of alpha-synuclein and synphilin-1 in yeast.

Biochemical Society Transactions, 39(5):1476{1481, 2011. ISSN 0300-5127.

[174] U.S. Department of Health and Human Services. Biosafety in microbiological and biomedical labo-

ratories. US. Government printing oce, Washington (D.C.), 3rd ed edition, 1993.

[175] Shigeyuki Kawai, Wataru Hashimoto, and Kousaku Murata. Transformation of Saccharomyces

cerevisiae and other fungi: methods and possible underlying mechanism. Bioengineered bugs, 1(6):

395{403, 2010. ISSN 1949-1026 (Electronic).

[176] R Daniel Gietz and Robin A Woods. Transformation of yeast by lithium acetate/single-stranded

carrier DNA/polyethylene glycol method. Methods in Enzymology, 350:87{96, 2002. ISSN 0076-

6879.

[177] Folahan. O Ayorinde et al. Analysis of some commercial polysorbate formulations using matrixassisted

laser desorption/ionization time-of- ight mass spectrometry. Rapid Communications in

Mass Spectrometry, 14(22):2116{2124, 2000. ISSN 0951-4198.

[178] Simona C Baicu and Michael J Taylor. Acid{base bu ering in organ preservation solutions as a

function of temperature: new parameters for comparing bu er capacity and eciency. Cryobiology,

45(1):33{48, 2002. ISSN 0011-2240.

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Universiteit of Hogeschool
KU Leuven
Thesis jaar
2019
Promotor(en)
Prof. Dr. Joris Winderickx