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Cysteine Cathepsins in Neurological Disorders

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Abstract

Increased proteolytic activity is a hallmark of several pathological processes, including neurodegeneration. Increased expression and activity of cathepsins, lysosomal cysteine proteases, during degeneration of the central nervous system is frequently reported. Recent studies reveal that a disturbed balance of their enzymatic activities is the first insult in brain aging and age-related diseases. Leakage of cathepsins from lysosomes, due to their membrane permeability, and activation of pro-apoptotic factors additionally contribute to neurodegeneration. Furthermore, in inflammation-induced neurodegeneration the cathepsins expressed in activated microglia play a pivotal role in neuronal death. The proteolytic activity of cysteine cathepsins is controlled by endogenous protein inhibitors—the cystatins—which evidently fail to perform their function in neurodegenerative processes. Exogenous synthetic inhibitors, which may augment their inhibitory potential, are considered as possible therapeutic tools for the treatment of neurological disorders.

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Abbreviations

6-OHDA:

6-hydroxydopamine

AD:

Alzheimer’s disease

ALS:

Amiotrophic lateral sclerosis

APP:

Amyloid precursor protein

Aβ:

Amyloid beta

CNS:

Central nervous system

EPM1:

Progressive myoclonic epilepsy type 1

HCHWA-I:

Hereditary cerebral haemorrhage with amyloidosis of Icelandic-type

HD:

Huntington’s disease

LPS:

Lipopolysaccharide

MHC:

Major histocompatibility complex

NCL:

Neuronal ceroid lipofuscinosis

NPC:

Niemann–Pick disease type C

NPY:

Neuropeptide Y

PD:

Parkinson’s disease

References

  1. Kazantsev AG (2007) Cellular pathways leading to neuronal dysfunction and degeneration. Drug News Perspect 20(8):501–509

    CAS  PubMed  Google Scholar 

  2. Cataldo AM, Nixon RA (1990) Enzymatically active lysosomal proteases are associated with amyloid deposits in Alzheimer brain. Proc Natl Acad Sci U S A 87(10):3861–3865

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Hook VYH (2006) Neuroproteases in peptide neurotransmission and neurodegenerative diseases - applications to drug discovery research. Biodrugs 20(2):105–119

    CAS  PubMed  Google Scholar 

  4. Haque A, Banik NL, Ray SK (2008) New insights into the roles of endolysosomal cathepsins in the pathogenesis of Alzheimer’s disease: cathepsin inhibitors as potential therapeutics. CNS Neurol Disord-Dr 7(3):270–277

    CAS  Google Scholar 

  5. Chen JJ, Lin F, Qin ZH (2008) The roles of the proteasome pathway in signal transduction and neurodegenerative diseases. Neurosci Bull 24(3):183–194

    CAS  PubMed  Google Scholar 

  6. Nakanishi H (2003) Neuronal and microglial cathepsins in aging and age-related diseases. Ageing Res Rev 2(4):367–381

    CAS  PubMed  Google Scholar 

  7. Reiser J, Adair B, Reinheckel T (2010) Specialized roles for cysteine cathepsins in health and disease. J Clin Invest 120(10):3421–3431

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Barrett AJ, Rawlings ND (2007) ‘Species’ of peptidases. Biol Chem 388(11):1151–1157

    CAS  PubMed  Google Scholar 

  9. Puente XS, Sanchez LM, Overall CM, Lopez-Otin C (2003) Human and mouse proteases: a comparative genomic approach. Nat Rev Genet 4(7):544–558

    CAS  PubMed  Google Scholar 

  10. Rawlings ND, Tolle DP, Barrett AJ (2004) MEROPS: the peptidase database. Nucleic Acids Res 32(Database issue):D160–D164

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Rawlings ND, Barrett AJ, Bateman A (2012) MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res 40(D1):D343–D350

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Stoka V, Turk B, Turk V (2005) Lysosomal cysteine proteases: structural features and their role in apoptosis. Iubmb Life 57(4–5):347–353

    CAS  PubMed  Google Scholar 

  13. Turk B, Turk D, Turk V (2000) Lysosomal cysteine proteases: more than scavengers. Bba-Protein Struct Mol 1477(1–2):98–111

    CAS  Google Scholar 

  14. Turk V, Turk B, Turk D (2001) Lysosomal cysteine proteases: facts and opportunities. Embo J 20(17):4629–4633

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Yasothornsrikul S, Greenbaum D, Medzihradszky KF, Toneff T, Bundey R, Miller R, Schilling B, Petermann I, Dehnert J, Logvinova A, Goldsmith P, Neveu JM, Lane WS, Gibson B, Reinheckel T, Peters C, Bogyo M, Hook V (2003) Cathepsin L in secretory vesicles functions as a prohormone-processing enzyme for production of the enkephalin peptide neurotransmitter. Proc Natl Acad Sci U S A 100(16):9590–9595

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Brix K, Dunkhorst A, Mayer K, Jordans S (2008) Cysteine cathepsins: cellular roadmap to different functions. Biochimie 90(2):194–207

    CAS  PubMed  Google Scholar 

  17. Goulet B, Baruch A, Moon NS, Poirier M, Sansregret LL, Erickson A, Bogyo M, Nepveu A (2004) A cathepsin L isoform that is devoid of a signal peptide localizes to the nucleus in S phase and processes the CDP/Cux transcription factor. Mol Cell 14(2):207–219

    CAS  PubMed  Google Scholar 

  18. Muller S, Dennemarker J, Reinheckel T (2012) Specific functions of lysosomal proteases in endocytic and autophagic pathways. Bba-Proteins Proteom 1824(1):34–43

    Google Scholar 

  19. Friedrichs B, Tepel C, Reinheckel T, Deussing J, von Figura K, Herzog V, Peters C, Saftig P, Brix K (2003) Thyroid functions of mouse cathepsins B, K, and L. J Clin Invest 111(11):1733–1745

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Funkelstein L, Toneff T, Hwang SR, Reinheckel T, Peters C, Hook V (2008) Cathepsin L participates in the production of neuropeptide Y in secretory vesicles, demonstrated by protease gene knockout and expression. J Neurochem 106(1):384–391

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Funkelstein L, Toneff T, Mosier C, Hwang SR, Beuschlein F, Lichtenauer UD, Reinheckel T, Peters C, Hook V (2008) Major role of cathepsin L for producing the peptide hormones ACTH, beta-endorphin, and alpha-MSH, illustrated by protease gene knockout and expression. J Biol Chem 283(51):35652–35659

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Honey K, Rudensky AY (2003) Lysosomal cysteine proteases regulate antigen presentation. Nat Rev Immunol 3(6):472–482

    CAS  PubMed  Google Scholar 

  23. Chapman HA, Riese RJ, Shi GP (1997) Emerging roles for cysteine proteases in human biology. Annu Rev Physiol 59:63–88. doi:10.1146/annurev.physiol.59.1.63

    CAS  PubMed  Google Scholar 

  24. Yasuda Y, Kaleta J, Bromme D (2005) The role of cathepsins in osteoporosis and arthritis: rationale for the design of new therapeutics. Adv Drug Deliv Rev 57(7):973–993

    CAS  PubMed  Google Scholar 

  25. Turk B, Stoka V, Rozman-Pungercar J, Cirman T, Droga-Mazovec G, Oreic K, Turk V (2002) Apoptotic pathways: involvement of lysosomal proteases. Biol Chem 383(7–8):1035–1044

    CAS  PubMed  Google Scholar 

  26. Tanabe H, Kumagai N, Tsukahara T, Ishiura S, Kominami E, Nishina H, Sugita H (1991) Changes of lysosomal proteinase activities and their expression in rat cultured keratinocytes during differentiation. Biochim Biophys Acta 1094(3):281–287

    CAS  PubMed  Google Scholar 

  27. Kos J, Lah TT (1998) Cysteine proteinases and their endogenous inhibitors: target proteins for prognosis, diagnosis and therapy in cancer (Review). Oncol Rep 5(6):1349–1361

    CAS  PubMed  Google Scholar 

  28. Conus S, Simon HU (2008) Cathepsins: key modulators of cell death and inflammatory responses. Biochem Pharmacol 76(11):1374–1382

    CAS  PubMed  Google Scholar 

  29. Kawada A, Hara KJ, Kominami E, Hiruma M, Noguchi H, Ishibashi A (1997) Processing of cathepsins L, B and D in psoriatic epidermis. Arch Dermatol Res 289(2):87–93

    CAS  PubMed  Google Scholar 

  30. Takeda A, Jimi T, Wakayama Y, Misugi N, Miyake S, Kumagai T (1992) Demonstration of cathepsins B, H and L in xenografts of normal and Duchenne-muscular-dystrophy muscles transplanted into nude-mice. Biochem J 288:643–648

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Liu J, Sukhova GK, Yang JT, Sun JS, Ma LK, Ren A, Xu WH, Fu HX, Dolganov GM, Hu CC, Libby P, Shi GP (2006) Cathepsin L expression and regulation in human abdominal aortic aneurysm, atherosclerosis, and vascular cells. Atherosclerosis 184(2):302–311

    CAS  PubMed  Google Scholar 

  32. Stoch SA, Wagner JA (2008) Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clin Pharmacol Ther 83(1):172–176

    CAS  PubMed  Google Scholar 

  33. Halangk W, Lerch MM, Brandt-Nedelev B, Roth W, Ruthenbuerger M, Reinheckel T, Domschke W, Lippert H, Peters C, Deussing J (2000) Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis. J Clin Invest 106(6):773–781

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Kos J, Sekirnik A, Premzl A, Bergant VZ, Langerholc T, Turk B, Werle B, Golouh R, Repnik U, Jeras M, Turk V (2005) Carboxypeptidases cathepsins X and B display distinct protein profile in human cells and tissues. Exp Cell Res 306(1):103–113

    CAS  PubMed  Google Scholar 

  35. Kos J, Jevnikar Z, Obermajer N (2009) The role of cathepsin X in cell signaling. Cell Adhes Migr 3(2):164–166

    Google Scholar 

  36. Bernstein HG, Kirschke H, Wiederanders B, Schmidt D, Rinne A (1990) Antigenic expression of cathepsin-B in aged human brain. Brain Res Bull 24(4):543–549

    CAS  PubMed  Google Scholar 

  37. Nakanishi H, Tominaga K, Amano T, Hirotsu I, Inoue T, Yamamoto K (1994) Age-related changes in activities and localizations of cathepsins D, E, B, and L in the rat brain tissues. Exp Neurol 126(1):119–128

    CAS  PubMed  Google Scholar 

  38. Petanceska S, Burke S, Watson SJ, Devi L (1994) Differential distribution of messenger RNAs for cathepsins B, L and S in adult rat brain: an in situ hybridization study. Neuroscience 59(3):729–738

    CAS  PubMed  Google Scholar 

  39. Tang CH, Lee JW, Galvez MG, Robillard L, Mole SE, Chapman HA (2006) Murine cathepsin F deficiency causes neuronal lipofuscinosis and late-onset neurological disease. Mol Cell Biol 26(6):2309–2316

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Wendt W, Zhu XR, Lubbert H, Stichel CC (2007) Differential expression of cathepsin X in aging and pathological central nervous system of mice. Exp Neurol 204(2):525–540

    CAS  PubMed  Google Scholar 

  41. Koike M, Shibata M, Ezaki J, Peters C, Saftig P, Kominami E, Uchiyama Y (2013) Differences in expression patterns of cathepsin C/dipeptidyl peptidase I in normal, pathological and aged mouse central nervous system. Eur J Neurosci 37(5):816–830

    PubMed  Google Scholar 

  42. Liuzzo JP, Petanceska SS, Moscatelli D, Devi LA (1999) Inflammatory mediators regulate cathepsin S in macrophages and microglia: a role in attenuating heparan sulfate interactions. Mol Med 5(5):320–333

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Funkelstein L, Lu WD, Koch B, Mosier C, Toneff T, Taupenot L, O’Connor DT, Reinheckel T, Peters C, Hook V (2012) Human cathepsin V protease participates in production of enkephalin and NPY neuropeptide neurotransmitters. J Biol Chem 287(19):15232–15241

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Pope A, Nixon RA (1984) Proteases of human-brain. Neurochem Res 9(3):291–323

    CAS  PubMed  Google Scholar 

  45. Spizz G, Blackshear PJ (1997) Identification and characterization of cathepsin B as the cellular MARCKS cleaving enzyme. J Biol Chem 272(38):23833–23842

    CAS  PubMed  Google Scholar 

  46. Hook VYH, Toneff T, Aaron W, Yasothornsrikul S, Bundey R, Reisine T (2002) Beta-amyloid peptide in regulated secretory vesicles of chromaffin cells: evidence for multiple cysteine proteolytic activities in distinct pathways for beta-secretase activity in chromaffin vesicles. J Neurochem 81(2):237–256

    CAS  PubMed  Google Scholar 

  47. Hook VYH, Reisine TD (2003) Cysteine proteases are the major beta-secretase in the regulated secretory pathway that provides most of the beta-amyloid in Alzheimer’s disease: role of BACE 1 in the constitutive secretory pathway. J Neurosci Res 74(3):393–405

    CAS  PubMed  Google Scholar 

  48. Kindy MS, Yu J, Zhu H, El-Amouri SS, Hook V, Hook GR (2012) Deletion of the cathepsin B gene improves memory deficits in a transgenic ALZHeimer’s disease mouse model expressing AbetaPP containing the wild-type beta-secretase site sequence. J Alzheimers Dis 29(4):827–840

    CAS  PubMed  Google Scholar 

  49. Authier F, Metioui M, Bell AW, Mort JS (1999) Negative regulation of epidermal growth factor signaling by selective proteolytic mechanisms in the endosome mediated by cathepsin B. J Biol Chem 274(47):33723–33731

    CAS  PubMed  Google Scholar 

  50. Authier F, Kouach M, Briand G (2005) Endosomal proteolysis of insulin-like growth factor-I at its C-terminal D-domain by cathepsin B. Febs Lett 579(20):4309–4316

    CAS  PubMed  Google Scholar 

  51. Ryan RE, Sloane BF, Sameni M, Wood PL (1995) Microglial cathepsin-B - an immunological examination of cellular and secreted species. J Neurochem 65(3):1035–1045

    CAS  PubMed  Google Scholar 

  52. Kingham PJ, Pocock JM (2001) Microglial secreted cathepsin B induces neuronal apoptosis. J Neurochem 76(5):1475–1484

    CAS  PubMed  Google Scholar 

  53. Schotte P, Van Criekinge W, Van de Craen M, Van Loo G, Desmedt M, Grooten J, Cornelissen M, De Ridder L, Vandekerckhove J, Fiers W, Vandenabeele P, Beyaert R (1998) Cathepsin B-mediated activation of the proinflammatory caspase-11. Biochem Biophys Res Commun 251(1):379–387

    CAS  PubMed  Google Scholar 

  54. Benchoua A, Braudeau J, Reis A, Couriaud C, Onteniente B (2004) Activation of proinflammatory caspases by cathepsin B in focal cerebral ischemia. J Cereb Blood Flow Metab 24(11):1272–1279

    CAS  PubMed  Google Scholar 

  55. Cirman T, Snipas SJ, Ellerby LM, Bredesen D, Freeze H, Abrahamson M, Bromme D, Krajewski S, Reed JC, Yin XM, Turk V, Salvesen GS (2001) Lysosomal protease pathways to apoptosis: cleavage of Bid, not pro-caspases, is the most likely route. J Biol Chem 276(5):3149–3157

    PubMed  Google Scholar 

  56. Cirman T, Oresic K, Mazovec GD, Turk V, Reed JC, Myers RM, Salvesen GS, Turk B (2004) Selective disruption of lysosomes in HeLa cells triggers apoptosis mediated by cleavage of bid by multiple papain-like lysosomal cathepsins. J Biol Chem 279(5):3578–3587

    CAS  PubMed  Google Scholar 

  57. Guicciardi ME, Deussing J, Miyoshi H, Bronk SF, Svingen PA, Peters C, Kaufmann SH, Gores GJ (2000) Cathepsin B contributes to TNF-alpha-mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c. J Clin Invest 106(9):1127–1137

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Yakovlev AA, Gorokhovatsky AY, Onufriev MV, Beletsky IP, Gulyaeva NV (2008) Brain cathepsin B cleaves a caspase substrate. Biochem-Moscow+ 73(3):332–336

    CAS  Google Scholar 

  59. Funkelstein L, Beinfeld M, Minokadeh A, Zadina J, Hook V (2010) Unique biological function of cathepsin L in secretory vesicles for biosynthesis of neuropeptides. Neuropeptides 44(6):457–466

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Hook V, Funkelstein L, Wegrzyn J, Bark S, Kindy M, Hook G (2012) Cysteine cathepsins in the secretory vesicle produce active peptides: cathepsin L generates peptide neurotransmitters and cathepsin B produces beta-amyloid of Alzheimer’s disease. Bba-Proteins Proteom 1824(1):89–104

    CAS  Google Scholar 

  61. Stahl S, Reinders Y, Asan E, Mothes W, Conzelmann E, Sickmann A, Felbor U (2007) Proteomic-analysis of cathepsin B and L-deficient mouse brain lysosomes. Bba-Proteins Proteom 1774(10):1237–1246

    CAS  Google Scholar 

  62. Lu WD, Funkelstein L, Toneff T, Reinheckel T, Peters C, Hook V (2012) Cathepsin H functions as an aminopeptidase in secretory vesicles for production of enkephalin and galanin peptide neurotransmitters. J Neurochem 122(3):512–522

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Brguljan PM, Turk V, Cimerman N, Brzin J, Krizaj I, Popovic A (2003) Human brain cathepsin H as a neuropeptide and bradykinin metabolizing enzyme. Peptides 24(12):1977–1984

    CAS  PubMed  Google Scholar 

  64. Nagler DK, Menard R (1998) Human cathepsin X: A novel cysteine protease of the papain family with a very short proregion and unique insertions. Febs Lett 434(1–2):135–139

    CAS  PubMed  Google Scholar 

  65. Obermajer N, Doljak B, Kos J (2006) Cysteine cathepsins: regulators of antitumour immune response. Expert Opin Biol Ther 6(12):1295–1309

    CAS  PubMed  Google Scholar 

  66. Obermajer N, Doljak B, Jamnik P, Fonovic UP, Kos J (2009) Cathepsin X cleaves the C-terminal dipeptide of alpha- and gamma-enolase and impairs survival and neuritogenesis of neuronal cells. Int J Biochem Cell B 41(8–9):1685–1696

    CAS  Google Scholar 

  67. Pišlar AH, Zidar N, Kikelj D, Kos J (2013) Cathepsin X promotes 6-hydroxydopamine-induced apoptosis of PC12 and SH-SY5Y cells. Neuropharmacology. doi:10.1016/j.neuropharm.2013.07.040

  68. Petanceska S, Canoll P, Devi LA (1996) Expression of rat cathepsin S in phagocytic cells. J Biol Chem 271(8):4403–4409

    CAS  PubMed  Google Scholar 

  69. Wendt W, Lubbert H, Stichel CC (2008) Upregulation of cathepsin S in the aging and pathological nervous system of mice. Brain Res 1232:7–20

    CAS  PubMed  Google Scholar 

  70. Nakanishi H (2003) Microglial functions and proteases. Mol Neurobiol 27(2):163–176

    CAS  PubMed  Google Scholar 

  71. Kirschke H, Wiederanders B (1994) Cathepsin-S and related lysosomal endopeptidases. Method Enzymol 244:500–511

    CAS  Google Scholar 

  72. Kirschke H, Wiederanders B, Bromme D, Rinne A (1989) Cathepsin-S from bovine spleen—purification, distribution, intracellular-localization and action on proteins. Biochem J 264(2):467–473

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Maciewicz RA, Etherington DJ (1988) A comparison of four cathepsins (B, L, N and S) with collagenolytic activity from rabbit spleen. Biochem J 256(2):433–440

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Shi GP, Munger JS, Meara JP, Rich DH, Chapman HA (1992) Molecular-cloning and expression of human alveolar macrophage cathepsin-S, an elastinolytic cysteine protease. J Biol Chem 267(11):7258–7262

    CAS  PubMed  Google Scholar 

  75. Hao HP, Doh-ura K, Nakanishi H (2007) Impairment of microglial responses to facial nerve axotomy in cathepsin S-deficient mice. J Neurosci Res 85(10):2196–2206

    CAS  PubMed  Google Scholar 

  76. Lindstedt L, Lee M, Oorni K, Bromme D, Kovanen PT (2003) Cathepsins F and S block HDL3-induced cholesterol efflux from macrophage foam cells. Biochem Biophys Res Commun 312(4):1019–1024

    CAS  PubMed  Google Scholar 

  77. Oorni K, Sneck M, Bromme D, Pentikainen MO, Lindstedt KA, Mayranpaa M, Aitio H, Kovanen PT (2004) Cysteine protease cathepsin F is expressed in human atherosclerotic lesions, is secreted by cultured macrophages, and modifies low density lipoprotein particles in vitro. J Biol Chem 279(33):34776–34784

    PubMed  Google Scholar 

  78. Cataldo AM, Paskevich PA, Kominami E, Nixon RA (1991) Lysosomal hydrolases of different classes are abnormally distributed in brains of patients with Alzheimer disease. Proc Natl Acad Sci U S A 88(24):10998–11002

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Cataldo AM, Hamilton DJ, Nixon RA (1994) Lysosomal abnormalities in degenerating neurons link neuronal compromise to senile plaque development in Alzheimer disease. Brain Res 640(1–2):68–80

    CAS  PubMed  Google Scholar 

  80. Cataldo AM, Hamilton DJ, Barnett JL, Paskevich PA, Nixon RA (1996) Abnormalities of the endosomal-lysosomal system in Alzheimer’s disease: relationship to disease pathogenesis. Adv Exp Med Biol 389:271–280

    CAS  PubMed  Google Scholar 

  81. Lynch G, Bi XN (2003) Lysosomes and brain aging in mammals. Neurochem Res 28(11):1725–1734

    CAS  PubMed  Google Scholar 

  82. Mantle D, Falkous G, Ishiura S, Perry RH, Perry EK (1995) Comparison of cathepsin protease activities in brain tissue from normal cases and cases with Alzheimer’s disease, Lewy body dementia, Parkinson’s disease and Huntington’s disease. J Neurol Sci 131(1):65–70

    CAS  PubMed  Google Scholar 

  83. Nakamura Y, Takeda M, Suzuki H, Morita H, Tada K, Hariguchi S, Nishimura T (1989) Lysosome instability in aged rat brain. Neurosci Lett 97(1–2):215–220

    CAS  PubMed  Google Scholar 

  84. Yamashima T (2000) Implication of cysteine proteases calpain, cathepsin and caspase in ischemic neuronal death of primates. Prog Neurobiol 62(3):273–295

    CAS  PubMed  Google Scholar 

  85. Nixon RA, Cataldo AM (1993) The lysosomal system in neuronal cell-death: a review. Ann NY Acad Sci 679:87–109

    CAS  PubMed  Google Scholar 

  86. Felbor U, Kessler B, Mothes W, Goebel HH, Ploegh HL, Bronson RT, Olsen BR (2002) Neuronal loss and brain atrophy in mice lacking cathepsins B and L. Proc Natl Acad Sci U S A 99(12):7883–7888

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Nagai A, Murakawa Y, Terashima M, Shimode K, Umegae N, Takeuchi H, Kobayashi S (2000) Cystatin C and cathepsin B in CSF from patients with inflammatory neurologic diseases. Neurology 55(12):1828–1832

    CAS  PubMed  Google Scholar 

  88. Stichel CC, Luebbert H (2007) Inflammatory processes in the aging mouse brain: participation of dendritic cells and T-cells. Neurobiol Aging 28(10):1507–1521

    CAS  PubMed  Google Scholar 

  89. Hafner A, Glavan G, Obermajer N, Zivin M, Schliebs R, Kos J (2013) Neuroprotective role of gamma-enolase in microglia in a mouse model of Alzheimer’s disease is regulated by cathepsin X. Aging Cell 12(4):604–614

    CAS  PubMed  Google Scholar 

  90. Bednarski E, Ribak CE, Lynch G (1997) Suppression of cathepsins B and L causes a proliferation of lysosomes and the formation of meganeurites in hippocampus. J Neurosci 17(11):4006–4021

    CAS  PubMed  Google Scholar 

  91. Cataldo AM, Barnett JL, Mann DMA, Nixon RA (1996) Colocalization of lysosomal hydrolase and beta-amyloid in diffuse plaques of the cerebellum and striatum in Alzheimer’s disease and Down’s syndrome. J Neuropathol Exp Neurol 55(6):704–715

    CAS  PubMed  Google Scholar 

  92. Lemere CA, Munger JS, Shi GP, Natkin L, Haass C, Chapman HA, Selkoe DJ (1995) The lysosomal cysteine protease, cathepsin-S, is increased in Alzheimers-disease and Down syndrome brain: an immunocytochemical study. Am J Pathol 146(4):848–860

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Ii K, Ito H, Kominami E, Hirano A (1993) Abnormal distribution of cathepsin proteinases and endogenous inhibitors (cystatins) in the hippocampus of patients with Alzheimer’s disease, parkinsonism-dementia complex on Guam, and senile dementia and in the aged. Virchows Arch A Pathol Anat Histopathol 423(3):185–194

    CAS  PubMed  Google Scholar 

  94. Bernstein HG, Kirschke H, Wiederanders B, Pollak KH, Zipress A, Rinne A (1996) The possible place of cathepsins and cystatins in the puzzle of Alzheimer disease: a review. Mol Chem Neuropathol 27(3):225–247

    CAS  PubMed  Google Scholar 

  95. Schechter I, Ziv E (2011) Cathepsins S, B and L with aminopeptidases display beta-secretase activity associated with the pathogenesis of Alzheimer’s disease. Biol Chem 392(6):555–569

    CAS  PubMed  Google Scholar 

  96. Hook VY, Kindy M, Hook G (2008) Inhibitors of cathepsin B improve memory and reduce beta-amyloid in transgenic Alzheimer disease mice expressing the wild-type, but not the Swedish mutant, beta-secretase site of the amyloid precursor protein. J Biol Chem 283(12):7745–7753

    CAS  PubMed  Google Scholar 

  97. Hook G, Hook V, Kindy M (2011) The cysteine protease inhibitor, E64d, reduces brain amyloid-beta and improves memory deficits in Alzheimer’s disease animal models by inhibiting cathepsin B, but not BACE1, beta-secretase activity. J Alzheimers Dis 26(2):387–408

    CAS  PubMed  Google Scholar 

  98. Hook VY, Kindy M, Reinheckel T, Peters C, Hook G (2009) Genetic cathepsin B deficiency reduces beta-amyloid in transgenic mice expressing human wild-type amyloid precursor protein. Biochem Biophys Res Commun 386(2):284–288

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Mueller-Steiner S, Zhou Y, Arai H, Roberson ED, Sun BG, Chen J, Wang X, Yu GQ, Esposito L, Mucke L, Gan L (2006) Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer’s disease. Neuron 51(6):703–714

    CAS  PubMed  Google Scholar 

  100. Lee S, Sato Y, Nixon RA (2011) Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer’s-like axonal dystrophy. J Neurosci 31(21):7817–7830

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Yamashima T, Oikawa S (2009) The role of lysosomal rupture in neuronal death. Prog Neurobiol 89(4):343–358

    CAS  PubMed  Google Scholar 

  102. Bendiske J, Bahr BA (2003) Lysosomal activation is a compensatory response against protein accumulation and associated synaptopathogenesis - an approach for slowing Alzheimer disease? J Neuropathol Exp Neurol 62(5):451–463

    CAS  PubMed  Google Scholar 

  103. Munger JS, Haass C, Lemere CA, Shi GP, Wong WSF, Teplow DB, Selkoe DJ, Chapman HA (1995) Lysosomal processing of amyloid precursor protein to a-beta peptides: a distinct role for cathepsin-S. Biochem J 311:299–305

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Liuzzo JP, Petanceska SS, Devi LA (1999) Neurotrophic factors regulate cathepsin S in macrophages and microglia: a role in the degradation of myelin basic protein and amyloid beta peptide. Mol Med 5(5):334–343

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW (1993) Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J Neurosci 13(4):1676–1687

    CAS  PubMed  Google Scholar 

  106. Brunk U, Brun A (1972) The effect of aging on lysosomal permeability in nerve cells of the central nervous system. An enzyme histochemical study in rat. Histochemie 30(4):315–324

    CAS  PubMed  Google Scholar 

  107. Bahr BA, Bendiske J (2002) The neuropathogenic contributions of lysosomal dysfunction. J Neurochem 83(3):481–489

    CAS  PubMed  Google Scholar 

  108. Tardy C, Andrieu-Abadie N, Salvayre R, Levade T (2004) Lysosomal storage diseases: is impaired apoptosis a pathogenic mechanism? Neurochem Res 29(5):871–880

    CAS  PubMed  Google Scholar 

  109. Nixon RA, Cataldo AM (2006) Lysosomal system pathways: genes to neurodegeneration in Alzheimer’s disease. J Alzheimers Dis 9(3 Suppl):277–289

    CAS  PubMed  Google Scholar 

  110. Vellodi A (2005) Lysosomal storage disorders. Br J Haematol 128(4):413–431

    CAS  PubMed  Google Scholar 

  111. Koike M, Shibata M, Waguri S, Yoshimura K, Tanida I, Kominami E, Gotow T, Peters C, von Figura K, Mizushima N, Saftig P, Uchiyama Y (2005) Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease). Am J Pathol 167(6):1713–1728

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Nitatori T, Sato N, Waguri S, Karasawa Y, Araki H, Shibanai K, Kominami E, Uchiyama Y (1995) Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. J Neurosci 15(2):1001–1011

    CAS  PubMed  Google Scholar 

  113. Amritraj A, Peake K, Kodam A, Salio C, Merighi A, Vance JE, Kar S (2009) Increased activity and altered subcellular distribution of lysosomal enzymes determine neuronal vulnerability in Niemann–Pick type C1-deficient mice. Am J Pathol 175(6):2540–2556

    CAS  PubMed Central  PubMed  Google Scholar 

  114. McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38(8):1285–1291

    CAS  PubMed  Google Scholar 

  115. Amano T, Nakanishi H, Kondo T, Tanaka T, Oka M, Yamamoto K (1995) Age-related changes in cellular localization and enzymatic activities of cathepsins B, L and D in the rat trigeminal ganglion neuron. Mech Ageing Dev 83(3):133–141

    CAS  PubMed  Google Scholar 

  116. Wendt W, Schulten R, Stichel CC, Lubbert H (2009) Intra- versus extracellular effects of microglia-derived cysteine proteases in a conditioned medium transfer model. J Neurochem 110(6):1931–1941

    CAS  PubMed  Google Scholar 

  117. Batchelor PE, Liberatore GT, Wong JYF, Porritt MJ, Frerichs F, Donnan GA, Howells DW (1999) Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum sand express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J Neurosci 19(5):1708–1716

    CAS  PubMed  Google Scholar 

  118. Gonzalez-Scarano F, Baltuch G (1999) Microglia as mediators of inflammatory and degenerative diseases. Annu Rev Neurosci 22:219–240

    CAS  PubMed  Google Scholar 

  119. Fan K, Wu XF, Fan B, Li N, Lin YZ, Yao YW, Ma JM (2012) Up-regulation of microglial cathepsin C expression and activity in lipopolysaccharide-induced neuroinflammation. J Neuroinflammation 9:96

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Czapski GA, Gajkowska B, Strosznajder JB (2010) Systemic administration of lipopolysaccharide induces molecular and morphological alterations in the hippocampus. Brain Res 1356:85–94

    CAS  PubMed  Google Scholar 

  121. Matyszak MK, Perry VH (1996) The potential role of dendritic cells in immune-mediated inflammatory diseases in the central nervous system. Neuroscience 74(2):599–608

    CAS  PubMed  Google Scholar 

  122. Pashenkov M, Teleshova N, Link H (2003) Inflammation in the central nervous system: the role for dendritic cells. Brain Pathol 13(1):23–33

    PubMed  Google Scholar 

  123. Beck H, Schwarz G, Schroter CJ, Deeg M, Baier D, Stevanovic S, Weber E, Driessen C, Kalbacher H (2001) Cathepsin S and an asparagine-specific endoprotease dominate the proteolytic processing of human myelin basic protein in vitro. Eur J Immunol 31(12):3726–3736

    CAS  PubMed  Google Scholar 

  124. Fissolo N, Kraus M, Reich M, Ayturan M, Overkleeft H, Driessen C, Weissert R (2008) Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation. Eur J Immunol 38(9):2401–2411

    CAS  PubMed  Google Scholar 

  125. Pradhan S, Andreasson K (2013) Commentary: Progressive inflammation as a contributing factor to early development of Parkinson’s disease. Exp Neurol 241:148–155

    PubMed  Google Scholar 

  126. Lotharius J, Brundin P (2002) Pathogenesis of Parkinson’s disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci 3(12):932–942

    CAS  PubMed  Google Scholar 

  127. Chung KK, Dawson VL, Dawson TM (2003) New insights into Parkinson’s disease. J Neurol 250(Suppl 3):III15–III24

    PubMed  Google Scholar 

  128. Lee DC, Close FT, Goodman CB, Jackson IM, Wight-Mason C, Wells LM, Womble TA, Palm DE (2006) Enhanced cystatin C and lysosomal protease expression following 6-hydroxydopamine exposure. Neurotoxicology 27(2):260–276

    CAS  PubMed  Google Scholar 

  129. Li LY, Wang XX, Fei XF, Xia LP, Qin ZH, Liang ZQ (2011) Parkinson’s disease involves autophagy and abnormal distribution of cathepsin L. Neurosci Lett 489(1):62–67

    CAS  PubMed  Google Scholar 

  130. Xiang B, Fei XF, Zhuang WZ, Fang Y, Qin ZH, Liang ZQ (2011) Cathepsin L is involved in 6-hydroxydopamine induced apoptosis of SH-SY5Y neuroblastoma cells. Brain Res 1387:29–38

    CAS  PubMed  Google Scholar 

  131. Akopyan T (1991) Protein inhibitors of proteinases from brain. Neurochem Res 16(5):513–517

    CAS  PubMed  Google Scholar 

  132. Avanzo P, Sabotic J, Anzlovar S, Popovic T, Leonardi A, Pain RH, Kos J, Brzin J (2009) Trypsin-specific inhibitors from the basidiomycete Clitocybe nebularis with regulatory and defensive functions. Microbiol-Sgm 155:3971–3981

    CAS  Google Scholar 

  133. Lenarcic B, Bevec T (1998) Thyropins – New structurally related proteinase inhibitors. Biol Chem 379(2):105–111

    CAS  PubMed  Google Scholar 

  134. Bevec T, Stoka V, Pungercic G, Dolenc I, Turk V (1996) Major histocompatibility complex class II-associated p41 invariant chain fragment is a strong inhibitor of lysosomal cathepsin L. J Exp Med 183(4):1331–1338

    CAS  PubMed  Google Scholar 

  135. Bevec T, Stoka V, Pungercic G, Cazzulo JJ, Turk V (1997) A fragment of the major histocompatibility complex class II-associated p41 invariant chain inhibits cruzipain, the major cysteine proteinase from Trypanosoma cruzi. Febs Lett 401(2–3):259–261

    CAS  PubMed  Google Scholar 

  136. Abrahamson M, Barrett AJ, Salvesen G, Grubb A (1986) Isolation of six cysteine proteinase inhibitors from human urine. Their physicochemical and enzyme kinetic properties and concentrations in biological fluids. J Biol Chem 261(24):11282–11289

    CAS  PubMed  Google Scholar 

  137. Bode W, Engh R, Musil D, Thiele U, Huber R, Karshikov A, Brzin J, Kos J, Turk V (1988) The 2.0 a X-Ray crystal-structure of chicken egg-white cystatin and its possible mode of interaction with cysteine proteinases. Embo J 7(8):2593–2599

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Alvarez-Fernandez M, Barrett AJ, Gerhartz B, Dando PM, Ni JA, Abrahamson M (1999) Inhibition of mammalian legumain by some cystatins is due to a novel second reactive site. J Biol Chem 274(27):19195–19203

    CAS  PubMed  Google Scholar 

  139. Brown WM, Dziegielewska KM (1997) Friends and relations of the cystatin superfamily - new members and their evolution. Protein Sci 6(1):5–12

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Laitala-Leinonen T, Rinne R, Saukko P, Vaananen HK, Rinne A (2006) Cystatin B as an intracellular modulator of bone resorption. Matrix Biol 25(3):149–157

    CAS  PubMed  Google Scholar 

  141. Colbert JD, Matthews SP, Miller G, Watts C (2009) Diverse regulatory roles for lysosomal proteases in the immune response. Eur J Immunol 39(11):2955–2965

    CAS  PubMed  Google Scholar 

  142. Wallin H, Bjarnadottir M, Vogel LK, Wasselius J, Ekstrom U, Abrahamson M (2010) Cystatins - Extra- and intracellular cysteine protease inhibitors: high-level secretion and uptake of cystatin C in human neuroblastoma cells. Biochimie 92(11):1625–1634

    CAS  PubMed  Google Scholar 

  143. Langerholc T, Zavasnik-Bergant V, Turk B, Turk V, Abrahamson M, Kos J (2005) Inhibitory properties of cystatin F and its localization in U937 promonocyte cells. Febs J 272(6):1535–1545

    CAS  PubMed  Google Scholar 

  144. Magister S, Obermajer N, Mirkovic B, Svajger U, Renko M, Softic A, Romih R, Colbert JD, Watts C, Kos J (2012) Regulation of cathepsins S and L by cystatin F during maturation of dendritic cells. Eur J Cell Biol 91(5):391–401

    CAS  PubMed  Google Scholar 

  145. Premzl A, Zavasnik-Bergant V, Turk V, Kos J (2003) Intracellular and extracellular cathepsin B facilitate invasion of MCF-10A neoT cells through reconstituted extracellular matrix in vitro. Exp Cell Res 283(2):206–214

    CAS  PubMed  Google Scholar 

  146. Sundelof J, Arnlov J, Ingelsson E, Sundstrom J, Basu S, Zethelius B, Larsson A, Irizarry MC, Giedraitis V, Ronnemaa E, Degerman-Gunnarsson M, Hyman BT, Basun H, Kilander L, Lannfelt L (2008) Serum cystatin C and the risk of Alzheimer disease in elderly men. Neurology 71(14):1072–1079

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Sun BG, Zhou YG, Halabisky B, Lo I, Cho SH, Mueller-Steiner S, Devidze N, Wang X, Grubb A, Gan L (2008) Cystatin C-cathepsin B axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer’s disease. Neuron 60(2):247–257

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Kaeser SA, Herzig MC, Coomaraswamy J, Kilger E, Selenica ML, Winkler DT, Staufenbiel M, Levy E, Grubb A, Jucker M (2007) Cystatin C modulates cerebral beta-amyloidosis. Nat Genet 39(12):1437–1439

    CAS  PubMed  Google Scholar 

  149. Irani DN, Anderson C, Gundry R, Cotter R, Moore S, Kerr DA, McArthur JC, Sacktor N, Pardo CA, Jones M, Calabresi PA, Nath A (2006) Cleavage of cystatin C in the cerebrospinal fluid of patients with multiple sclerosis. Ann Neurol 59(2):237–247

    CAS  PubMed  Google Scholar 

  150. Hansson SF, Simonsen AH, Zetterberg H, Andersen O, Haghighi S, Fagerberg I, Andreasson U, Westman-Brinkmalm A, Wallin A, Ruetschi U, Blennow K (2007) Cystatin C in cerebrospinal fluid and multiple sclerosis. Ann Neurol 62(2):193–196

    CAS  PubMed  Google Scholar 

  151. Xu L, Sheng JS, Tang ZS, Wu XF, Yu Y, Guo H, Shen Y, Zhou CF, Paraoan L, Zhou JW (2005) Cystatin C prevents degeneration of rat nigral dopaminergic neurons: in vitro and in vivo studies. Neurobiol Dis 18(1):152–165

    CAS  PubMed  Google Scholar 

  152. Wilson ME, Boumaza I, Lacomis D, Bowser R (2010) Cystatin C: a candidate biomarker for amyotrophic lateral sclerosis. Plos One 5(12):e15133

    PubMed Central  PubMed  Google Scholar 

  153. D’Adamio L (2010) Role of Cystatin C in neuroprotection and its therapeutic implications. Am J Pathol 177(5):2163–2165

    PubMed Central  PubMed  Google Scholar 

  154. Pennacchio LA, Lehesjoki AE, Stone NE, Willour VL, Virtaneva K, Miao J, D’Amato E, Ramirez L, Faham M, Koskiniemi M, Warrington JA, Norio R, de la Chapelle A, Cox DR, Myers RM (1996) Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1). Science 271(5256):1731–1734

    CAS  PubMed  Google Scholar 

  155. Lalioti MD, Scott HS, Buresi C, Rossier C, Bottani A, Morris MA, Malafosse A, Antonarakis SE (1997) Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy. Nature 386(6627):847–851

    CAS  PubMed  Google Scholar 

  156. Kaur G, Mohan P, Pawlik M, DeRosa S, Fajiculay J, Che SL, Grubb A, Ginsberg SD, Nixon RA, Levy E (2010) Cystatin C rescues degenerating neurons in a cystatin B-knockout mouse model of progressive myoclonus epilepsy. Am J Pathol 177(5):2256–2267

    CAS  PubMed Central  PubMed  Google Scholar 

  157. Houseweart MK, Pennacchio LA, Vilaythong A, Peters C, Noebels JL, Myers RM (2003) Cathepsin B but not cathepsins L or S contributes to the pathogenesis of Unverricht-Lundborg progressive myoclonus epilepsy (EPM1). J Neurobiol 56(4):315–327

    CAS  PubMed  Google Scholar 

  158. Polajnar M, Ceru S, Kopitar-Jerala N, Zerovnik E (2012) Human stefin B normal and patho-physiological role: molecular and cellular aspects of amyloid-type aggregation of certain EPM1 mutants. Front Mol Neurosci 5:88

    CAS  PubMed Central  PubMed  Google Scholar 

  159. Revesz T, Holton JL, Lashley T, Plant G, Frangione B, Rostagno A, Ghiso J (2009) Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies. Acta Neuropathol 118(1):115–130

    CAS  PubMed Central  PubMed  Google Scholar 

  160. Cohen DH, Feiner H, Jensson O, Frangione B (1983) Amyloid fibril in hereditary cerebral-hemorrhage with amyloidosis (HCHWA) is related to the gastroentero-pancreatic neuroendocrine protein, gamma trace. J Exp Med 158(2):623–628

    CAS  PubMed  Google Scholar 

  161. Wei LH, Berman Y, Castano EM, Cadene M, Beavis RC, Devi L, Levy E (1998) Instability of the amyloidogenic cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type. J Biol Chem 273(19):11806–11814

    CAS  PubMed  Google Scholar 

  162. Hook G, Hook VY, Kindy M (2007) Cysteine protease inhibitors reduce brain beta-amyloid and beta-secretase activity in vivo and are potential Alzheimer’s disease therapeutics. Biol Chem 388(9):979–983

    CAS  PubMed  Google Scholar 

  163. Hook V, Hook G, Kindy M (2010) Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce beta-amyloid related to Alzheimer’s disease. Biol Chem 391(8):861–872

    CAS  PubMed  Google Scholar 

  164. Van Broeck B, Van Broeckhoven C, Kumar-Singh S (2007) Current insights into molecular mechanisms of Alzheimer disease and their implications for therapeutic approaches. Neurodegener Dis 4(5):349–365

    PubMed  Google Scholar 

  165. Kikuchi H, Yamada T, Furuya H, Doh-ura K, Ohyagi Y, Iwaki T, Kira J (2003) Involvement of cathepsin B in the motor neuron degeneration of amyotrophic lateral sclerosis. Acta Neuropathol 105(5):462–468

    CAS  PubMed  Google Scholar 

  166. Ratovitski T, Chighladze E, Waldron E, Hirschhorn RR, Ross CA (2011) Cysteine proteases bleomycin hydrolase and cathepsin Z mediate N-terminal proteolysis and toxicity of mutant huntingtin. J Biol Chem 286(14):12578–12589

    CAS  PubMed Central  PubMed  Google Scholar 

  167. Liang Q, Ouyang X, Schneider L, Zhang J (2011) Reduction of mutant huntingtin accumulation and toxicity by lysosomal cathepsins D and B in neurons. Mol Neurodegener 6:37

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The authors sincerely acknowledge Prof. Roger Pain for the critical review of the manuscript. This project was supported by a grant from Research Agency of the Republic of Slovenia (grants P4-0127 and J4-4123 to JK).

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  1. Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia

    Anja Pišlar & Janko Kos

  2. Department of Biotechnology, Jožef Stefan Institute, Jamova 39, 1000, Ljubljana, Slovenia

    Janko Kos

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  1. Anja Pišlar
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Correspondence to Anja Pišlar or Janko Kos.

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Pišlar, A., Kos, J. Cysteine Cathepsins in Neurological Disorders. Mol Neurobiol 49, 1017–1030 (2014). https://doi.org/10.1007/s12035-013-8576-6

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