Supporting Appendix 2: Confounding Linked to parkin (Park2)

Unless Parkin-deficient mice are compared to control mice on a coisogenic background, there could be systematic and biased differences in genes linked to parkin that could cause phenotypes mistakenly attributed to the parkin mutation. Targeted parkin alleles have been generated using ES cells from 129 mouse strains. When mice carrying these targeted parkin alleles are crossed to the B6 mouse strain, the targeted mutant parkin allele becomes a marker for the 129-derived ; the untargeted parkin allele becomes a marker for the B6 chromosome. On average, genes within a 12-20 cM region of the parkin could still be 129 derived in Parkin-deficient mice even after 10-15 backcrosses to B6 mice; the corresponding genes would be B6 derived in control mice (1-3). In earlier backcross generations, this region of difference could be significantly larger (~30 cM after 6 backcrosses). In F2 B6;129 mice, the region of difference could be >60 cM. Moreover, it could take 50 backcrosses to B6 mice to reduce the region of difference between congenic Parkin-deficient and control mice to a ~4 cM region spanning parkin (3). There could be considerable genetic differences between 129 and B6 mice in this relatively small region of the mouse genome (4). Strain differences in genes linked to targeted alleles can produce phenotypes unrelated to the targeted mutation. For example, after 10 backcrosses to create a congenic B6 strain, mice with a targeted deletion of the Il10 gene exhibited reduced exploratory behavior in the open field test (which would be consistent with parkinsonism). This behavioral finding was not due to the Il10 deletion; it was caused by strain differences (129 vs. B6) in a gene linked to the Il10 mutant allele (5). Although these potential confounds apply to many studies using genetically engineered mice, it is of particular concern in Parkin-deficient mice due to the intensity of investigation, the subtle and inconsistent phenotypes, the centromeric location of parkin, and the specific identity of genes linked to parkin. The region of the mouse genome containing parkin, also known as the t complex and located near the MHC , is enriched for genes involved in development (6). Within this region there are recombination “cold spots”, from approximately 6.5 to 8 cM for example, where the apparent recombination rates are lower than expected for a random process (7, 8). There are also numerous candidate genes closely linked to parkin that could explain the reported phenotypes in Parkin-deficient mice tested on a B6;129 hybrid genetic background; these genes are very likely 129 derived in Parkin-deficient mice and B6 derived in control mice. In many of these cases, creating Parkin-deficient mice on a congenic B6 background (12 backcrosses) will not fully address the problem because the region of difference, 12-20 cM, still contains confounding genes. Genes of particular concern linked to the parkin locus are identified in the chart below with approximate linkage map distances reported relative to the centromere of Chromosome 17. The parkin gene has been placed at ~6 cM. The chart provides numbered references that illustrate how some of the phenotypes reported in Parkin- deficient mice could be attributed to strain differences (129 vs. B6) in genes closely linked to parkin. References documenting polymorphisms with functional consequences between strains of mice for several of these genes are also provided. Potential confounds of future studies using Parkin-deficient mice on non-coisogenic backgrounds are also identified. Although many examples of potential confounds are illustrated, this

FA Perez and RD Palmiter 1

list is not exhaustive; there are additional genes linked to parkin that could further confound interpretation. The genes linked to parkin were identified using the following resources: Mouse Genome Informatics web site (http://www.informatics.jax.org/), UCSC Mouse Genome Bioinformatics web site (http://genome.ucsc.edu/), and NCBI Map Viewer (http://www.ncbi.nlm.nih.gov).

Please see the chart on the following page that summarizes the specific confounding genes linked to parkin.

References 1. Gerlai, R. (1996) Trends Neurosci 19, 177-81. 2. Gerlai, R. (2001) Behav Brain Res 125, 13-21. 3. Flaherty, L. (1981) in The Mouse in Biomedical Research, eds. Foster, H. L., Small, J. D. & Fox, J. G. (Academic Press, New York), Vol. 1, pp. 215-222. 4. Wade, C. M., Kulbokas, E. J., 3rd, Kirby, A. W., Zody, M. C., Mullikin, J. C., Lander, E. S., Lindblad-Toh, K. & Daly, M. J. (2002) Nature 420, 574-8. 5. Bolivar, V. J., Cook, M. N. & Flaherty, L. (2001) Genome Res 11, 1549-52. 6. Ko, M. S., Threat, T. A., Wang, X., Horton, J. H., Cui, Y., Pryor, E., Paris, J., Wells-Smith, J., Kitchen, J. R., Rowe, L. B., Eppig, J., Satoh, T., Brant, L., Fujiwara, H., Yotsumoto, S. & Nakashima, H. (1998) Hum Mol Genet 7, 1967-78. 7. Schalkwyk, L. C., Weiher, M., Kirby, M., Cusack, B., Himmelbauer, H. & Lehrach, H. (1998) Mamm Genome 9, 807-11. 8. Himmelbauer, H. & Silver, L. M. (1993) Genomics 17, 110-20.

FA Perez and RD Palmiter 2 D e cre a Iro A sed M I m e n De n ylo ta cre m a L b Nig cre mp In e o a e id cre a li se ro a t p h rn c se ab ro De De e S in d s a ta De o m tria d S o te cre cre ta se g r u lism m rtl a m a t o sc in De d e- n ficit it r ia lfa P a a in e d och k l ro e d se se e n r m s i e sig ct p in ep cre -i d e r o te ti d d nd ur sp n o s aso b th o a b e n o n ry b ili e sit s o lo u a o m so d f a ty t s Ne ed d com ce n nse o o lin m io y t ce ry p m ria xid ul u u n d a g b e o b ro o b e lo p t l d p NE d n s o m o o h h o a h e ta n r d to co n e e sen ysfu tive e ysfu ur n a cle y we p r g n no n t l su e a m rip o o c o ia a ra cti typ typ sa nct stre t o n to rvi r o y n ct xi ni a ig tu vit ti te ti io p te io g v n h r on st e e on ss e n n ra a ce Gene Symbol cM t e y s s n s t n s l mitochondrial factor B1 Tfb1m, 4 (30) (30) cocaine induced activation 3 QTL Cocia3 4 (18) obesity QTL 4 Obq4 4 (1) (1) NADPH oxidase 3 Nox3 4 (37) phosphodiesterase 10A Pde10a 5 (24,25) (24,25) quaking Qk 6 parkin Park2 6 (57,59,61) (57) (57) (57) (61) (60,61) (57) (58) (59) (59) (57,58) (60) bulb size 4 QTL Bulb4 7 (42) plasminogen Plg 7 (2,3,4,5) (2,23) (2,26,27) (2,38) (2,45) (2,53,54,55) solute carrier family 22, members 1-3 Slc22a1, 2, and 3 7 (46,47,48) acetyl-Coenzyme A acetyltransferases 2 and 3 Acat2 and Acat3 8 (31) (56) superoxide dismutase 2, mitochondrial Sod2 8 (32,33,34,35) (32,33,34,35) (32,33,49) subunit, beta type 1 Psmb1 8 (43) behavioral response to methamphetamines 10 QTL Brmth10 10 (19) glutamate receptor, metabotropic 4 Grm4 13 (28,29) (39) peroxisome proliferator activator receptor delta Ppard 14 (6,7,8) (6,7,8) body weight, 3 weeks, QTL 3 Wt3q3 14 (9) (9) NADH-ubiquinone oxidoreductase subunit B14.5a Ndufa7 18 (36) proteasome subunit, beta type 9 Psmb9 19 (43,44) proteasome subunit, beta type 8 Psmb8 19 (43,44) Tnf 19 (10,11,12,13) (10,11,12,14,15) (10,11,12,20) (10,11,12,13) (10,11,12,20,50) gamma-aminobutyric acid (GABA-B) receptor, 1 Gabbr1 20 (16) (21) (16) (16) (40,41) ventral midbrain iron content 9 QTL Vmbic9 23 (51) locomotor activity 2 QTL Loco2 23 (17) vascular endothelial growth factor A Vegfa 24 (52) cocaine induced activation 13 QTL Cocia13 25 (22)

Chart of confounding genes linked to parkin (Park2). The phenotypes that have been reported (with references identified along the Park2 row) or could be reported in Parkin-deficient mice are identified along the top of the table. Strain differences in genes closely linked to parkin could explain these phenotypes. Numbers reflect references (listed below) that support the role of a parkin-linked gene in a phenotype relevant to the study of Parkin-deficient mice. Distances (cM) are from the centromere of mouse Chromosome 17; parkin is at ~6 cM. Park2 could be considered a candidate gene for some of the QTLs presented; however, studies using Parkin-deficient mice on a B6;129 genetic background are not informative and data using coisogenic Parkin-deficient mice (129S4) are not supportive.

FA Perez and RD Palmiter 3 1. Taylor BA, Phillips SJ (1997) Obesity QTLs on mouse 2 and 17. Genomics 43:249-257. 2. Degen SJ, Bell SM, Schaefer LA, Elliott RW (1990) Characterization of the cDNA coding for mouse plasminogen and localization of the gene to mouse chromosome 17. Genomics 8:49-61. 3. Hoover-Plow J, Wang N, Ploplis V (1999) Growth and behavioral development in plasminogen gene-targeted mice. Growth Dev Aging 63:13-32. 4. Hoover-Plow J, Ellis J, Yuen L (2002) In vivo plasminogen deficiency reduces fat accumulation. Thromb Haemost 87:1011-1019. 5. Wang N, Zhang L, Miles L, Hoover-Plow J (2004a) Plasminogen regulates pro- opiomelanocortin processing. J Thromb Haemost 2:785-796. 6. Jones PS, Savory R, Barratt P, Bell AR, Gray TJ, Jenkins NA, Gilbert DJ, Copeland NG, Bell DR (1995) Chromosomal localisation, inducibility, tissue- specific expression and strain differences in three murine peroxisome- proliferator-activated-receptor genes. Eur J Biochem 233:219-226. 7. Luquet S, Lopez-Soriano J, Holst D, Fredenrich A, Melki J, Rassoulzadegan M, Grimaldi PA (2003) Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability. Faseb J 17:2299-2301. 8. Wang YX, Zhang CL, Yu RT, Cho HK, Nelson MC, Bayuga-Ocampo CR, Ham J, Kang H, Evans RM (2004b) Regulation of Muscle Fiber Type and Running Endurance by PPARdelta. PLoS Biol 2:e294. 9. Moody DE, Pomp D, Nielsen MK, Van Vleck LD (1999) Identification of quantitative trait loci influencing traits related to energy balance in selection and inbred lines of mice. Genetics 152:699-711. 10. Niizeki H, Inoko H, Wayne Streilein J (2002) Polymorphisms in the TNF region confer susceptibility to UVB-induced impairment of contact hypersensitivity induction in mice and humans. Methods 28:46-54. 11. Jongeneel CV, Acha-Orbea H, Blankenstein T (1990) A polymorphic microsatellite in the tumor necrosis factor alpha promoter identifies an allele unique to the NZW mouse strain. J Exp Med 171:2141-2146. 12. Freund YR, Sgarlato G, Jacob CO, Suzuki Y, Remington JS (1992) Polymorphisms in the tumor necrosis factor alpha (TNF-alpha) gene correlate with murine resistance to development of toxoplasmic encephalitis and with levels of TNF-alpha mRNA in infected brain tissue. J Exp Med 175:683-688. 13. Ventre J, Doebber T, Wu M, MacNaul K, Stevens K, Pasparakis M, Kollias G, Moller DE (1997) Targeted disruption of the tumor necrosis factor-alpha gene: metabolic consequences in obese and nonobese mice. Diabetes 46:1526-1531. 14. Hale KD, Weigent DA, Gauthier DK, Hiramoto RN, Ghanta VK (2003) and hormone profiles in mice subjected to handling combined with rectal temperature measurement stress and handling only stress. Life Sci 72:1495- 1508. 15. Long NC, Vander AJ, Kunkel SL, Kluger MJ (1990) Antiserum against tumor necrosis factor increases stress hyperthermia in rats. Am J Physiol 258:R591- 595. 16. Schuler V, Luscher C, Blanchet C, Klix N, Sansig G, Klebs K, Schmutz M, Heid J, Gentry C, Urban L, Fox A, Spooren W, Jaton AL, Vigouret J, Pozza M, Kelly PH,

FA Perez and RD Palmiter 4 Mosbacher J, Froestl W, Kaslin E, Korn R, Bischoff S, Kaupmann K, van der Putten H, Bettler B (2001) Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABA(B) responses in mice lacking GABA(B(1)). Neuron 31:47-58. 17. Furuse T, Takano-Shimizu T, Moriwaki K, Shiroishi T, Koide T (2002) QTL analyses of spontaneous activity by using mouse strains from Mishima battery. Mamm Genome 13:411-415. 18. Boyle AE, Gill K (2001) Sensitivity of AXB/BXA recombinant inbred lines of mice to the locomotor activating effects of cocaine: a quantitative trait loci analysis. Pharmacogenetics 11:255-264. 19. Grisel JE, Belknap JK, O'Toole LA, Helms ML, Wenger CD, Crabbe JC (1997) Quantitative trait loci affecting methamphetamine responses in BXD recombinant inbred mouse strains. J Neurosci 17:745-754. 20. Nakajima A, Yamada K, Nagai T, Uchiyama T, Miyamoto Y, Mamiya T, He J, Nitta A, Mizuno M, Tran MH, Seto A, Yoshimura M, Kitaichi K, Hasegawa T, Saito K, Yamada Y, Seishima M, Sekikawa K, Kim HC, Nabeshima T (2004) Role of tumor necrosis factor-alpha in methamphetamine-induced drug dependence and neurotoxicity. J Neurosci 24:2212-2225. 21. Zhou W, Mailloux AW, Jung BJ, Edmunds HS, Jr., McGinty JF (2004) GABAB receptor stimulation decreases amphetamine-induced behavior and neuropeptide in the striatum. Brain Res 1004:18-28. 22. Gill KJ, Boyle AE (2003) Confirmation of quantitative trait loci for cocaine-induced activation in the AcB/BcA series of recombinant congenic strains. Pharmacogenetics 13:329-338. 23. Hoover-Plow J, Skomorovska-Prokvolit O, Welsh S (2001) Selective behaviors altered in plasminogen-deficient mice are reconstituted with intracerebroventricular injection of plasminogen. Brain Res 898:256-264. 24. Seeger TF, Bartlett B, Coskran TM, Culp JS, James LC, Krull DL, Lanfear J, Ryan AM, Schmidt CJ, Strick CA, Varghese AH, Williams RD, Wylie PG, Menniti FS (2003) Immunohistochemical localization of PDE10A in the rat brain. Brain Res 985:113-126. 25. O'Connor V, Genin A, Davis S, Karishma KK, Doyere V, De Zeeuw CI, Sanger G, Hunt SP, Richter-Levin G, Mallet J, Laroche S, Bliss TV, French PJ (2004) Differential amplification of intron-containing transcripts reveals long term potentiation-associated up-regulation of specific Pde10A phosphodiesterase splice variants. J Biol Chem 279:15841-15849. 26. Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, Teng KK, Yung WH, Hempstead BL, Lu B (2004) Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306:487-491. 27. Nakagami Y, Abe K, Nishiyama N, Matsuki N (2000) Laminin degradation by plasmin regulates long-term potentiation. J Neurosci 20:2003-2010. 28. Pekhletski R, Gerlai R, Overstreet LS, Huang XP, Agopyan N, Slater NT, Abramow-Newerly W, Roder JC, Hampson DR (1996) Impaired cerebellar synaptic plasticity and motor performance in mice lacking the mGluR4 subtype of metabotropic glutamate receptor. J Neurosci 16:6364-6373.

FA Perez and RD Palmiter 5 29. Gerlai R, Roder JC, Hampson DR (1998) Altered spatial learning and memory in mice lacking the mGluR4 subtype of metabotropic glutamate receptor. Behav Neurosci 112:525-532. 30. Rantanen A, Gaspari M, Falkenberg M, Gustafsson CM, Larsson NG (2003) Characterization of the mouse genes for mitochondrial transcription factors B1 and B2. Mamm Genome 14:1-6. 31. Meiner VL, Cases S, Myers HM, Sande ER, Bellosta S, Schambelan M, Pitas RE, McGuire J, Herz J, Farese RV, Jr. (1996) Disruption of the acyl- CoA:cholesterol acyltransferase gene in mice: evidence suggesting multiple cholesterol esterification in mammals. Proc Natl Acad Sci U S A 93:14041-14046. 32. Schisler NJ, Singh SM (1985) Tissue-specific developmental regulation of superoxide dismutase (SOD-1 and SOD-2) activities in genetic strains of mice. Biochem Genet 23:291-308. 33. Guo Z, Higuchi K, Mori M (2003) Spontaneous hypomorphic mutations in antioxidant enzymes of mice. Free Radic Biol Med 35:1645-1652. 34. Williams MD, Van Remmen H, Conrad CC, Huang TT, Epstein CJ, Richardson A (1998) Increased oxidative damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice. J Biol Chem 273:28510-28515. 35. Kokoszka JE, Coskun P, Esposito LA, Wallace DC (2001) Increased mitochondrial oxidative stress in the Sod2 (+/-) mouse results in the age-related decline of mitochondrial function culminating in increased . Proc Natl Acad Sci U S A 98:2278-2283. 36. Ruiz-Lozano P, Smith SM, Perkins G, Kubalak SW, Boss GR, Sucov HM, Evans RM, Chien KR (1998) Energy deprivation and a deficiency in downstream metabolic target genes during the onset of embryonic in RXRalpha-/- embryos. Development 125:533-544. 37. Banfi B, Malgrange B, Knisz J, Steger K, Dubois-Dauphin M, Krause KH (2004) NOX3: A superoxide-generating NADPH oxidase of the inner ear. J Biol Chem. 38. Nagai T, Yamada K, Yoshimura M, Ishikawa K, Miyamoto Y, Hashimoto K, Noda Y, Nitta A, Nabeshima T (2004) The tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release. Proc Natl Acad Sci U S A 101:3650-3655. 39. Marino MJ, Williams DL, Jr., O'Brien JA, Valenti O, McDonald TP, Clements MK, Wang R, DiLella AG, Hess JF, Kinney GG, Conn PJ (2003) Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson's disease treatment. Proc Natl Acad Sci U S A 100:13668-13673. 40. Engberg G, Kling-Petersen T, Nissbrandt H (1993) GABAB-receptor activation alters the firing pattern of dopamine neurons in the rat substantia nigra. Synapse 15:229-238. 41. Engberg G, Elverfors A, Jonason J, Nissbrandt H (1997) Inhibition of dopamine re-uptake: significance for nigral dopamine neuron activity. Synapse 25:215-226. 42. Williams RW, Airey DC, Kulkarni A, Zhou G, Lu L (2001) Genetic dissection of the olfactory bulbs of mice: QTLs on four chromosomes modulate bulb size. Behav Genet 31:61-77.

FA Perez and RD Palmiter 6 43. Elenich LA, Nandi D, Kent AE, McCluskey TS, Cruz M, Iyer MN, Woodward EC, Conn CW, Ochoa AL, Ginsburg DB, Monaco JJ (1999) The complete primary structure of mouse 20S . Immunogenetics 49:835-842. 44. Diaz-Hernandez M, Hernandez F, Martin-Aparicio E, Gomez-Ramos P, Moran MA, Castano JG, Ferrer I, Avila J, Lucas JJ (2003) Neuronal induction of the immunoproteasome in Huntington's disease. J Neurosci 23:11653-11661. 45. Tsirka SE, Rogove AD, Bugge TH, Degen JL, Strickland S (1997) An extracellular proteolytic cascade promotes neuronal degeneration in the mouse hippocampus. J Neurosci 17:543-552. 46. Wu X, Kekuda R, Huang W, Fei YJ, Leibach FH, Chen J, Conway SJ, Ganapathy V (1998) Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. J Biol Chem 273:32776-32786. 47. Grundemann D, Liebich G, Kiefer N, Koster S, Schomig E (1999) Selective substrates for non-neuronal monoamine transporters. Mol Pharmacol 56:1-10. 48. Zwart R, Verhaagh S, Buitelaar M, Popp-Snijders C, Barlow DP (2001) Impaired activity of the extraneuronal monoamine transporter system known as uptake-2 in Orct3/Slc22a3-deficient mice. Mol Cell Biol 21:4188-4196. 49. Andreassen OA, Ferrante RJ, Dedeoglu A, Albers DW, Klivenyi P, Carlson EJ, Epstein CJ, Beal MF (2001) Mice with a partial deficiency of manganese superoxide dismutase show increased vulnerability to the mitochondrial toxins malonate, 3-nitropropionic acid, and MPTP. Exp Neurol 167:189-195. 50. Ferger B, Leng A, Mura A, Hengerer B, Feldon J (2004) Genetic ablation of tumor necrosis factor-alpha (TNF-alpha) and pharmacological inhibition of TNF- synthesis attenuates MPTP toxicity in mouse striatum. J Neurochem 89:822-833. 51. Jones BC, Reed CL, Hitzemann R, Wiesinger JA, McCarthy KA, Buwen JP, Beard JL (2003) Quantitative genetic analysis of ventral midbrain and liver iron in BXD recombinant inbred mice. Nutr Neurosci 6:369-377. 52. Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K, Van Dorpe J, Hellings P, Gorselink M, Heymans S, Theilmeier G, Dewerchin M, Laudenbach V, Vermylen P, Raat H, Acker T, Vleminckx V, Van Den Bosch L, Cashman N, Fujisawa H, Drost MR, Sciot R, Bruyninckx F, Hicklin DJ, Ince C, Gressens P, Lupu F, Plate KH, Robberecht W, Herbert JM, Collen D, Carmeliet P (2001) Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 28:131- 138. 53. Tucker HM, Kihiko M, Caldwell JN, Wright S, Kawarabayashi T, Price D, Walker D, Scheff S, McGillis JP, Rydel RE, Estus S (2000a) The plasmin system is induced by and degrades amyloid-beta aggregates. J Neurosci 20:3937-3946. 54. Tucker HM, Kihiko-Ehmann M, Wright S, Rydel RE, Estus S (2000b) Tissue plasminogen activator requires plasminogen to modulate amyloid-beta neurotoxicity and deposition. J Neurochem 75:2172-2177. 55. Melchor JP, Pawlak R, Strickland S (2003) The tissue plasminogen activator- plasminogen proteolytic cascade accelerates amyloid-beta (Abeta) degradation and inhibits Abeta-induced neurodegeneration. J Neurosci 23:8867-8871.

FA Perez and RD Palmiter 7 56. Hutter-Paier B, Huttunen HJ, Puglielli L, Eckman CB, Kim DY, Hofmeister A, Moir RD, Domnitz SB, Frosch MP, Windisch M, Kovacs DM (2004) The ACAT Inhibitor CP-113,818 Markedly Reduces Amyloid Pathology in a Mouse Model of Alzheimer's Disease. Neuron 44:227-238. 57. Itier JM, Ibanez P, Mena MA, Abbas N, Cohen-Salmon C, Bohme GA, Laville M, Pratt J, Corti O, Pradier L, Ret G, Joubert C, Periquet M, Araujo F, Negroni J, Casarejos MJ, Canals S, Solano R, Serrano A, Gallego E, Sanchez M, Denefle P, Benavides J, Tremp G, Rooney TA, Brice A, Garcia de Yebenes J (2003) Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet 12:2277-2291. 58. Goldberg MS, Fleming SM, Palacino JJ, Cepeda C, Lam HA, Bhatnagar A, Meloni EG, Wu N, Ackerson LC, Klapstein GJ, Gajendiran M, Roth BL, Chesselet MF, Maidment NT, Levine MS, Shen J (2003) Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem 278:43628-43635. 59. Palacino JJ, Sagi D, Goldberg MS, Krauss S, Motz C, Wacker M, Klose J, Shen J (2004) Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem 279:18614-18622. 60. Von Coelln R, Thomas B, Savitt JM, Lim KL, Sasaki M, Hess EJ, Dawson VL, Dawson TM (2004) Loss of locus coeruleus neurons and reduced startle in parkin null mice. Proc Natl Acad Sci U S A 101:10744-10749. 61.FA Perez and RD Palmiter

FA Perez and RD Palmiter 8