903
Views
37
CrossRef citations to date
0
Altmetric
Review

Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases

, &
Pages 1237-1245 | Received 02 Oct 2015, Accepted 22 Apr 2016, Published online: 13 May 2016

References

  • Hara-Hishimura I, Takeuchi Y, Inoue K, et al. Vesicle transport and processing of the precursor to 2S albumin in pumpkin. Plant J. 1993;4(5):793–800.
  • Dando PM, Fortunato M, Smith L, et al. Pig kidney legumain: an asparaginyl endopeptidase with restricted specificity. Biochem J. 1999;339(Pt 3):743–749.
  • Chen JM, Dando PM, Rawlings ND, et al. Cloning, isolation, and characterization of mammalian legumain, an asparaginyl endopeptidase. J Biol Chem. 1997;272(12):8090–8098.
  • Chen JM, Dando PM, Stevens RA, et al. Cloning and expression of mouse legumain, a lysosomal endopeptidase. Biochem J. 1998;335(Pt 1):111–117.
  • Rawlings ND, Barrett AJ. Families of cysteine peptidases. Methods Enzymol. 1993;244:461–486.
  • Chen JM, Rawlings ND, Stevens RA, et al. Identification of the active site of legumain links it to caspases, clostripain and gingipains in a new clan of cysteine endopeptidases. FEBS Lett. 1998;441(3):361–365.
  • Manoury B, Hewitt EW, Morrice N, et al. An asparaginyl endopeptidase processes a microbial antigen for class II MHC presentation. Nature. 1998;396(6712):695–699.
  • Li DN, Matthews SP, Antoniou AN, et al. Multistep autoactivation of asparaginyl endopeptidase in vitro and in vivo. J Biol Chem. 2003;278(40):38980–38990.
  • Shirahama-Noda K, Yamamoto A, Sugihara K, et al. Biosynthetic processing of cathepsins and lysosomal degradation are abolished in asparaginyl endopeptidase-deficient mice. J Biol Chem. 2003;278(35):33194–33199.
  • Manoury B, Mazzeo D, Fugger L, et al. Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP. Nat Immunol. 2002;3(2):169–174.
  • Manoury B, Mazzeo D, Li DN, et al. Asparagine endopeptidase can initiate the removal of the MHC class II invariant chain chaperone. Immunity. 2003;18(4):489–498.
  • Beck H, Schwarz G, Schroter CJ, et al. Cathepsin S and an asparagine-specific endoprotease dominate the proteolytic processing of human myelin basic protein in vitro. Eur J Immunol. 2001;31(12):3726–3736.
  • Sepulveda FE, Maschalidi S, Colisson R, et al. Critical role for asparagine endopeptidase in endocytic Toll-like receptor signaling in dendritic cells. Immunity. 2009;31(5):737–748.
  • Chen JM, Fortunato M, Stevens RA, et al. Activation of progelatinase A by mammalian legumain, a recently discovered cysteine proteinase. Biol Chem. 2001;382(5):777–783.
  • Sarandeses CS, Covelo G, Diaz-Jullien C, et al. Prothymosin alpha is processed to thymosin alpha 1 and thymosin alpha 11 by a lysosomal asparaginyl endopeptidase. J Biol Chem. 2003;278(15):13286–13293.
  • Patel N, Krishnan S, Offman MN, et al. A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase. J Clin Invest. 2009;119(7):1964–1973.
  • Morita Y, Araki H, Sugimoto T, et al. Legumain/asparaginyl endopeptidase controls extracellular matrix remodeling through the degradation of fibronectin in mouse renal proximal tubular cells. FEBS Lett. 2007;581(7):1417–1424.
  • Liu Z, Jang SW, Liu X, et al. Neuroprotective actions of PIKE-L by inhibition of SET proteolytic degradation by asparagine endopeptidase. Mol Cell. 2008;29(6):665–678.
  • Ye K, Snyder SH. PIKE GTPase: a novel mediator of phosphoinositide signaling. J Cell Sci. 2004;117(Pt 2):155–161.
  • Ye K. PIKE/nuclear PI 3-kinase signaling in preventing programmed cell death. J Cell Biochem. 2005;96(3):463–472.
  • Zhang Z, Song M, Liu X, et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nat Med. 2014;20(11):1254–1262.
  • Zhang Z, Song M, Liu X, et al. Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease. Nat Commun. 2015;6:8762. ••This article reports that AEP acts as a delta-secretase that cleaves APP after N373 and N585. The resultant APP586–695 fragment is a better substrate for BACE1 than full-length APP. Thus, the proteolysis of APP by AEP promotes Aβ production. Deletion of AEP from 5XFAD and APP/PS1 mouse model alleviates Aβ deposition and cognitive impairments.
  • Rosenmann H. Asparagine endopeptidase cleaves tau and promotes neurodegeneration. Nat Med. 2014;20(11):1236–1238.
  • Ma L, Shen YQ, Khatri HP, et al. The asparaginyl endopeptidase legumain is essential for functional recovery after spinal cord injury in adult zebrafish. PLoS One. 2014;9(4):e95098.
  • Maehr R, Hang HC, Mintern JD, et al. Asparagine endopeptidase is not essential for class II MHC antigen presentation but is required for processing of cathepsin L in mice. J Immunol. 2005;174(11):7066–7074.
  • Murthy RV, Arbman G, Gao J, et al. Legumain expression in relation to clinicopathologic and biological variables in colorectal cancer. Clin Cancer Res. 2005;11(6):2293–2299.
  • Liu C, Sun C, Huang H, et al. Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy. Cancer Res. 2003;63(11):2957–2964.
  • Choi SJ, Reddy SV, Devlin RD, et al. Identification of human asparaginyl endopeptidase (legumain) as an inhibitor of osteoclast formation and bone resorption. J Biol Chem. 1999;274(39):27747–27753.
  • Miller G, Matthews SP, Reinheckel T, et al. Asparagine endopeptidase is required for normal kidney physiology and homeostasis. Faseb J. 2011;25(5):1606–1617.
  • Erickson AH. Biosynthesis of lysosomal endopeptidases. J Cell Biochem. 1989;40(1):31–41.
  • Chan CB, Abe M, Hashimoto N, et al. Mice lacking asparaginyl endopeptidase develop disorders resembling hemophagocytic syndrome. Proc Natl Acad Sci U S A. 2009;106(2):468–473.
  • Jordan MB, Hildeman D, Kappler J, et al. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood. 2004;104(3):735–743.
  • Maschalidi S, Hässler S, Blanc F, et al. Asparagine endopeptidase controls anti-influenza virus immune responses through TLR7 activation. PLoS Pathog. 2012;8(8):e1002841–e41.
  • Back T, Hoehn M, Mies G, et al. Penumbral tissue alkalosis in focal cerebral ischemia: relationship to energy metabolism, blood flow, and steady potential. Ann Neurol. 2000;47(4):485–492.
  • Ishizaki T, Erickson A, Kuric E, et al. The asparaginyl endopeptidase legumain after experimental stroke. J Cereb Blood Flow Metab. 2010;30(10):1756–1766.
  • Rickhag M, Wieloch T, Gido G, et al. Comprehensive regional and temporal gene expression profiling of the rat brain during the first 24 h after experimental stroke identifies dynamic ischemia-induced gene expression patterns, and reveals a biphasic activation of genes in surviving tissue. J Neurochem. 2006;96(1):14–29.
  • Clerin V, Shih HH, Deng N, et al. Expression of the cysteine protease legumain in vascular lesions and functional implications in atherogenesis. Atherosclerosis. 2008;201(1):53–66.
  • Moss CX, Matthews SP, Lamont DJ, et al. Asparagine deamidation perturbs antigen presentation on class II major histocompatibility complex molecules. J Biol Chem. 2005;280(18):18498–18503.
  • Ling SC, Polymenidou M, Cleveland DW. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron. 2013;79(3):416–438.
  • Janssens J, Van Broeckhoven C. Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD-ALS spectrum disorders. Hum Mol Genet. 2013;22(R1):R77–87.
  • Arai T, Hasegawa M, Akiyama H, et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2006;351(3):602–611.
  • Igaz LM, Kwong LK, Xu Y, et al. Enrichment of C-terminal fragments in TAR DNA-binding protein-43 cytoplasmic inclusions in brain but not in spinal cord of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Am J Pathol. 2008;173(1):182–194.
  • Igaz LM, Kwong LK, Chen-Plotkin A, et al. Expression of TDP-43 C-terminal Fragments in Vitro Recapitulates Pathological Features of TDP-43 Proteinopathies. J Biol Chem. 2009;284(13):8516–8524.
  • Herskowitz JH, Gozal YM, Duong DM, et al. Asparaginyl endopeptidase cleaves TDP-43 in brain. Proteomics. 2012;12(15–16):2455–2463.
  • Lagier-Tourenne C, Polymenidou M, Cleveland DW. TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum Mol Genet. 2010;19(R1):R46–64.
  • Gamblin TC, Chen F, Zambrano A, et al. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc Natl Acad Sci U S A. 2003;100(17):10032–10037.
  • Johnson GV, Jope RS, Binder LI. Proteolysis of tau by calpain. Biochem Biophys Res Commun. 1989;163(3):1505–1511.
  • Litersky JM, Scott CW, Johnson GV. Phosphorylation, calpain proteolysis and tubulin binding of recombinant human tau isoforms. Brain Res. 1993;604(1–2):32–40.
  • Basurto-Islas G, Grundke-Iqbal I, Tung YC, et al. Activation of asparaginyl endopeptidase leads to Tau hyperphosphorylation in Alzheimer disease. J Biol Chem. 2013;288(24):17495–17507.
  • Ji ZS, Miranda RD, Newhouse YM, et al. Apolipoprotein E4 potentiates amyloid β peptide-induced lysosomal leakage and apoptosis in neuronal cells. J Biol Chem. 2002;277(24):21821–21828.
  • Ditaranto K, Tekirian TL, Yang AJ. Lysosomal membrane damage in soluble Aβ-mediated cell death in Alzheimer’s disease. Neurobiol Dis. 2001;8(1):19–31.
  • Yang AJ, Chandswangbhuvana D, Margol L, et al. Loss of endosomal/lysosomal membrane impermeability is an early event in amyloid Aβ1-42 pathogenesis. J Neurosci Res. 1998;52(6):691–698.
  • Simonsen A, McGuire J, Podust V, et al. A novel panel of cerebrospinal fluid biomarkers for the differential diagnosis of Alzheimer’s disease versus normal aging and frontotemporal dementia. Dement Geriatr Cogn Disord. 2007;24(6):434–440.
  • Hansson SF, Andréasson U, Wall M, et al. Reduced levels of amyloid-beta-binding proteins in cerebrospinal fluid from Alzheimer’s disease patients. J Alzheimers Dis. 2008;16(2):389–397.
  • Yates CM, Butterworth J, Tennant MC, et al. Enzyme activities in relation to pH and lactate in postmortem brain in Alzheimer-type and other dementias. J Neurochem. 1990;55(5):1624–1630.
  • Fang B, Wang D, Huang M, et al. Hypothesis on the relationship between the change in intracellular pH and incidence of sporadic Alzheimer’s disease or vascular dementia. Int J Neurosci. 2010;120(9):591–595.
  • Pirchl M, Humpel C. [Does acidosis in brain play a role in Alzheimer’s disease?]. Neuropsychiatrie: Klinik, Diagnostik, Therapie und Rehabilitation: Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater. 2008;23(3):187–192.
  • Forester BP, Berlow YA, Harper DG, et al. Age‐related changes in brain energetics and phospholipid metabolism. NMR Biomed. 2010;23(3):242–250.
  • Mandal PK, Akolkar H, Tripathi M. Mapping of hippocampal pH and neurochemicals from in vivo multi-voxel 31P study in healthy normal young male/female, mild cognitive impairment, and Alzheimer’s disease. J Alzheimer’s Dis. 2012;31(S3):S75–86.
  • Chohan MO, Khatoon S, Iqbal IG, et al. Involvement of I2PP2A in the abnormal hyperphosphorylation of tau and its reversal by Memantine. FEBS Lett. 2006;580(16):3973–3979.
  • Wang X, Blanchard J, Grundke-Iqbal I, et al. Alzheimer disease and amyotrophic lateral sclerosis: an etiopathogenic connection. Acta Neuropathol. 2014;127(2):243–256.
  • Wang X, Blanchard J, Kohlbrenner E, et al. The carboxy-terminal fragment of inhibitor-2 of protein phosphatase-2A induces Alzheimer disease pathology and cognitive impairment. FASEB J. 2010;24(11):4420–4432.
  • Arnaud L, Chen S, Liu F, et al. Mechanism of inhibition of PP2A activity and abnormal hyperphosphorylation of tau by I2(PP2A)/SET. FEBS Lett. 2011;585(17):2653–2659.
  • Chasseigneaux S, Clamagirand C, Huguet L, et al. Cytoplasmic SET induces tau hyperphosphorylation through a decrease of methylated phosphatase 2A. BMC Neurosci. 2014;15:82.
  • Oddo S, Caccamo A, Shepherd JD, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron. 2003;39(3):409–421.
  • Lee J, Bogyo M. Synthesis and evaluation of aza-peptidyl inhibitors of the lysosomal asparaginyl endopeptidase, legumain. Bioorg Med Chem Lett. 2012;22(3):1340–1343.
  • Niestroj AJ, Feussner K, Heiser U, et al. Inhibition of mammalian legumain by Michael acceptors and AzaAsn-halomethylketones. Biol Chem. 2002;383(7–8):1205–1214.
  • Gotz MG, James KE, Hansell E, et al. Aza-peptidyl Michael acceptors. A new class of potent and selective inhibitors of asparaginyl endopeptidases (legumains) from evolutionarily diverse pathogens. J Med Chem. 2008;51(9):2816–2832.
  • Lee J, Bogyo M. Development of near-infrared fluorophore (NIRF)-labeled activity-based probes for in vivo imaging of legumain. ACS Chem Biol. 2010;5(2):233–243.
  • Higgins C, Bouazzaoui S, Gaddale K, et al. P3 SAR exploration of biphenyl carbamate based Legumain inhibitors. Bioorg Med Chem Lett. 2014;24(11):2521–2524.
  • Pardridge WM. Drug transport across the blood-brain barrier. J Cerebr Blood F Met. 2012;32(11):1959–1972.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.