Advertisement

Widespread Expression of a Membrane-Tethered Version of the Soluble Lysosomal Enzyme Palmitoyl Protein Thioesterase-1

  • Charles Shyng
  • Shannon L. Macauley
  • Joshua T. Dearborn
  • Mark S. Sands
Research Report
Part of the JIMD Reports book series (JIMD, volume 36)

Abstract

“Cross-correction,” the transfer of soluble lysosomal enzymes between neighboring cells, forms the foundation for therapeutics of lysosomal storage disorders (LSDs). However, “cross-correction” poses a significant barrier to studying the role of specific cell types in LSD pathogenesis. By expressing the native enzyme in only one cell type, neighboring cell types are invariably corrected. In this study, we present a strategy to limit “cross-correction” of palmitoyl-protein thioesterase-1(PPT1), a lysosomal hydrolase deficient in Infantile Neuronal Ceroid Lipofuscinosis (INCL, Infantile Batten disease) to the lysosomal membrane via the C-terminus of lysosomal associated membrane protein-1 (LAMP1). Tethering PPT1 to the lysosomal membrane prevented “cross-correction” while allowing PPT1 to retain its enzymatic function and localization in vitro. A transgenic line harboring the lysosomal membrane-tethered PPT1 was then generated. We show that expression of lysosome-restricted PPT1 in vivo largely rescues the INCL biochemical, histological, and functional phenotype. These data suggest that lysosomal tethering of PPT1 via the C-terminus of LAMP1 is a viable strategy and that this general approach can be used to study the role of specific cell types in INCL pathogenesis, as well as other LSDs. Ultimately, understanding the role of specific cell types in the disease progression of LSDs will help guide the development of more targeted therapeutics.

One Sentence Synopsis: Tethering PPT1 to the lysosomal membrane is a viable strategy to prevent “cross-correction” and will allow for the study of specific cellular contributions in INCL pathogenesis.

Keywords

Infantile Batten disease Lysosomal storage disorders Neuronal ceroid lipofuscinosis Palmitoyl-protein thioesterase-1 Soluble lysosomal enzymes 

Notes

Acknowledgments

We thank J. Michael White (Transgenic Knockout Micro-Injection Core, WUSTL) for his help with generating the transgenic founders. We thank Dr. Anne Hennig (Vision Research Core, WUSTL) for her help with the electroretinography. In addition, we thank Dr. Bruno Benitez for his advice and technical assistance.

References

  1. Benitez BA, Cairns NJ, Schmidt RE et al (2015) Clinically early-stage CSPalpha mutation carrier exhibits remarkable terminal stage neuronal pathology with minimal evidence of synaptic loss. Acta Neuropathol Commun 3:73CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bible E, Gupta P, Hofmann SL, Cooper JD (2004) Regional and cellular neuropathology in the palmitoyl protein thioesterase-1 null mutant mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis 16:346–359CrossRefPubMedGoogle Scholar
  3. Bill CA, Nickoloff JA (2001) Spontaneous and ultraviolet light-induced direct repeat recombination in mammalian cells frequently results in repeat deletion. Mutat Res 487:41–50CrossRefPubMedGoogle Scholar
  4. Dahms NM, Lobel P, Kornfeld S (1989) Mannose 6-phosphate receptors and lysosomal enzyme targeting. J Biol Chem 264:12115–12118PubMedGoogle Scholar
  5. Dearborn JT, Harmon SK, Fowler SC et al (2015) Comprehensive functional characterization of murine infantile Batten disease including Parkinson-like behavior and dopaminergic markers. Sci Rep 5:12752CrossRefPubMedPubMedCentralGoogle Scholar
  6. Dull T, Zufferey R, Kelly M et al (1998) A third-generation lentivirus vector with a conditional packaging system. J Virol 72:8463–8471PubMedPubMedCentralGoogle Scholar
  7. Griffey M, Bible E, Vogler C et al (2004) Adeno-associated virus 2-mediated gene therapy decreases autofluorescent storage material and increases brain mass in a murine model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis 16:360–369CrossRefPubMedGoogle Scholar
  8. Griffey M, Macauley SL, Ogilvie JM, Sands MS (2005) AAV2-mediated ocular gene therapy for infantile neuronal ceroid lipofuscinosis. Mol Ther 12:413–421CrossRefPubMedGoogle Scholar
  9. Guarnieri FG, Arterburn LM, Penno MB, Cha Y, August JT (1993) The motif Tyr-X-X-hydrophobic residue mediates lysosomal membrane targeting of lysosome-associated membrane protein 1. J Biol Chem 268:1941–1946PubMedGoogle Scholar
  10. Gupta P, Soyombo AA, Atashband A et al (2001) Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. Proc Natl Acad Sci U S A 98:13566–13571CrossRefPubMedPubMedCentralGoogle Scholar
  11. Haltia M, Rapola J, Santavuori P, Keranen A (1973) Infantile type of so-called neuronal ceroid-lipofuscinosis. 2. Morphological and biochemical studies. J Neurol Sci 18:269–285CrossRefPubMedGoogle Scholar
  12. Haruyama N, Cho A, Kulkarni AB (2009) Overview: engineering transgenic constructs and mice. Curr Protoc Cell Biol. Chapter 19: Unit 19.10.Google Scholar
  13. Hendricks CA, Almeida KH, Stitt MS et al (2003) Spontaneous mitotic homologous recombination at an enhanced yellow fluorescent protein (EYFP) cDNA direct repeat in transgenic mice. Proc Natl Acad Sci U S A 100:6325–6330CrossRefPubMedPubMedCentralGoogle Scholar
  14. Joshi M, Keith Pittman H, Haisch C, Verbanac K (2008) Real-time PCR to determine transgene copy number and to quantitate the biolocalization of adoptively transferred cells from EGFP-transgenic mice. BioTechniques 45:247–258CrossRefPubMedGoogle Scholar
  15. Khaibullina A, Kenyon N, Guptill V et al (2012) In a model of Batten disease, palmitoyl protein thioesterase-1 deficiency is associated with brown adipose tissue and thermoregulation abnormalities. PLoS One 7:e48733CrossRefPubMedPubMedCentralGoogle Scholar
  16. Kielar C, Maddox L, Bible E et al (2007) Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis 25:150–162CrossRefPubMedGoogle Scholar
  17. Macauley SL, Wozniak DF, Kielar C, Tan Y, Cooper JD, Sands MS (2009) Cerebellar pathology and motor deficits in the palmitoyl protein thioesterase 1-deficient mouse. Exp Neurol 217:124–135CrossRefPubMedPubMedCentralGoogle Scholar
  18. Macauley SL, Pekny M, Sands MS (2011) The role of attenuated astrocyte activation in infantile neuronal ceroid lipofuscinosis. J Neurosci 31:15575–15585CrossRefPubMedPubMedCentralGoogle Scholar
  19. Marathe S, Miranda SR, Devlin C et al (2000) Creation of a mouse model for non-neurological (type B) Niemann-Pick disease by stable, low level expression of lysosomal sphingomyelinase in the absence of secretory sphingomyelinase: relationship between brain intra-lysosomal enzyme activity and central nervous system function. Hum Mol Genet 9:1967–1976CrossRefPubMedGoogle Scholar
  20. Neufeld EF (1980) The uptake of enzymes into lysosomes: an overview. Birth Defects Orig Artic Ser 16:77–84PubMedGoogle Scholar
  21. Neufeld EF, Fratantoni JC (1970) Inborn errors of mucopolysaccharide metabolism. Science 169:141–146CrossRefPubMedGoogle Scholar
  22. Neufeld EF, Sando GN, Garvin AJ, Rome LH (1977) The transport of lysosomal enzymes. J Supramol Struct 6:95–101CrossRefPubMedGoogle Scholar
  23. Roberts MS, Macauley SL, Wong AM et al (2012) Combination small molecule PPT1 mimetic and CNS-directed gene therapy as a treatment for infantile neuronal ceroid lipofuscinosis. J Inherit Metab Dis 35:847–857CrossRefPubMedPubMedCentralGoogle Scholar
  24. Rohrer J, Schweizer A, Russell D, Kornfeld S (1996) The targeting of Lamp1 to lysosomes is dependent on the spacing of its cytoplasmic tail tyrosine sorting motif relative to the membrane. J Cell Biol 132:565–576CrossRefPubMedGoogle Scholar
  25. Sands MS, Davidson BL (2006) Gene therapy for lysosomal storage diseases. Mol Ther 13:839–849CrossRefPubMedGoogle Scholar
  26. Santavuori P, Haltia M, Rapola J, Raitta C (1973) Infantile type of so-called neuronal ceroid-lipofuscinosis. 1. A clinical study of 15 patients. J Neurol Sci 18:257–267CrossRefPubMedGoogle Scholar
  27. Tikka S, Monogioudi E, Gotsopoulos A et al (2016) Proteomic profiling in the brain of CLN1 disease model reveals affected functional modules. Neruomol Med 18:109–133CrossRefGoogle Scholar
  28. Verkruyse LA, Hofmann SL (1996) Lysosomal targeting of palmitoyl-protein thioesterase. J Biol Chem 271:15831–15836CrossRefPubMedGoogle Scholar
  29. Vesa J, Hellsten E, Verkruyse LA et al (1995) Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Nature 376:584–587CrossRefPubMedGoogle Scholar
  30. Woloszynek JC, Coleman T, Semenkovich CF, Sands MS (2007) Lysosomal dysfunction results in altered energy balance. J Biol Chem 282:35765–35771CrossRefPubMedGoogle Scholar
  31. Wurtele H, Gusew N, Lussier R, Chartrand P (2005) Characterization of in vivo recombination activities in the mouse embryo. Mol Genet Genomics 273:252–263CrossRefPubMedGoogle Scholar
  32. Zufferey R, Dull T, Mandel RJ et al (1998) Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J Virol 72:9873–9880PubMedPubMedCentralGoogle Scholar

Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Charles Shyng
    • 1
  • Shannon L. Macauley
    • 2
  • Joshua T. Dearborn
    • 1
  • Mark S. Sands
    • 1
    • 3
    • 4
  1. 1.Department of Internal MedicineWashington University School of MedicineSt. LouisUSA
  2. 2.Department of NeurologyWashington University School of MedicineSt. LouisUSA
  3. 3.Department of GeneticsWashington University School of MedicineSt. LouisUSA
  4. 4.Hope Center for Neurological DisordersWashington University School of MedicineSt. LouisUSA

Personalised recommendations