Abstract
Cathepsin protease genes are necessary for protein homeostasis in normal brain development and function. The diversity of the 15 cathepsin protease activities raises the question of what are the human brain expression profiles of the cathepsin genes during development from prenatal and infancy to childhood, adolescence, and young adult stages. This study, therefore, evaluated the cathepsin gene expression profiles in 16 human brain regions during development by quantitative RNA-sequencing data obtained from the Allen Brain Atlas resource. Total expression of all cathepsin genes was the lowest at the early prenatal stage which became increased at the infancy stage. During infancy to young adult phases, total gene expression was similar. Interestingly, the rank ordering of gene expression among the cathepsins was similar throughout the brain at the age periods examined, showing (a) high expression of cathepsins B, D, and F; (b) moderate expression of cathepsins A, L, and Z; (c) low expression of cathepsins C, H, K, O, S, and V; and (d) very low expression of cathepsins E, G, and W. Results show that the human brain utilizes well-defined, balanced patterns of cathepsin gene expression throughout the different stages of human brain development. Knowledge gained by this study of the gene expression profiles of lysosomal cathepsin proteases among human brain regions during normal development is important for advancing future investigations of how these cathepsins are dysregulated in lysosomal-related brain disorders that affect infants, children, adolescents, and young adults.
Similar content being viewed by others
References
Allan ERO, Campden RI, Ewanchuk BW, Tailor P, Balce DR, McKenna NT, Yates RM (2017) A role for cathepsin Z in neuroinflammation provides mechanistic support for an epigenetic risk factor in multiple sclerosis. J Neuroinflammation 14:103
Barrett AJ, Rawlings ND, Woessner JF (2004) Handbook of proteolytic enzymes, 2nd edn. Elsevier Academic Press, Amsterdam
Bernstein HG, Bogerts B, Lendeckel U (2008) Cathepsin K and metabolic abnormalities in schizophrenia. Arterioscler Thromb Vasc Biol 28:e163
Czibere L, Baur LA, Wittmann A, Gemmeke K, Steiner A, Weber P, Deussing JM (2011) Profiling trait anxiety: transcriptome analysis reveals cathepsin B (Ctsb) as a novel candidate gene for emotionality in mice. PLoS One 6:e23604
Dauth S, Sîrbulescu RF, Jordans S, Rehders M, Avena L, Oswald J, Brix K (2011) Cathepsin K deficiency in mice induces structural and metabolic changes in the central nervous system that are associated with learning and memory deficits. BMC Neurosci 12:74
de Magalhães JP, Curado J, Church GM (2009) Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics 25:875–881
Doccini S, Sartori S, Maeser S, Pezzini F, Rossato S, Moro F, Simonati A (2016) Early infantile neuronal ceroid lipofuscinosis (CLN10 disease) associated with a novel mutation in CTSD. J Neurol 263:1029–1032
Funkelstein L, Lu WD, Koch B, Mosier C, Toneff T, Taupenot L, Hook V (2012) Human cathepsin V protease participates in production of enkephalin and NPY neuropeptide neurotransmitters. J Biol Chem 287:15232–15241
Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, Miller JA, Jones AR (2012) An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 489:391–399
Hook V, Bandeira N (2015) Neuropeptidomics mass spectrometry reveals signaling networks generated by distinct protease pathways in human systems. J Am Soc Mass Spectrom 26:1970–1980
Hook GR, Yu J, Sipes N, Pierschbacher MD, Hook V, Kindy MS (2014a) The cysteine protease cathepsin B is a key drug target and cysteine protease inhibitors are potential therapeutics for traumatic brain injury. J Neurotrauma 31:515–529
Hook G, Yu J, Toneff T, Kindy M, Hook V (2014b) Brain pyroglutamate amyloid-β is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer’s disease therapeutic. J Alzheimers Dis 41:129–149
Hook G, Jacobsen JS, Grabstein K, Kindy M, Hook V (2015) Cathepsin B is a new drug target for traumatic brain injury therapeutics: evidence for E64d as a promising lead drug candidate. Front Neurol 6:178
Jeyakumar M, Dwek RA, Butters TD, Platt FM (2005) Storage solutions: treating lysosomal disorders of the brain. Nat Rev Neurosci 6:713–725
Ketscher A, Ketterer S, Dollwet-Mack S, Reif U, Reinheckel T (2016) Neuroectoderm-specific deletion of cathepsin D in mice models human inherited neuronal ceroid lipofuscinosis type 10. Biochimie 122:219–226
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 105:462–468
Kilinc M, Gürsoy-Ozdemir Y, Gürer G, Erdener SE, Erdemli E, Can A, Dalkara T (2010) Lysosomal rupture, necroapoptotic interactions and potential crosstalk between cysteine proteases in neurons shortly after focal ischemia. Neurobiol Dis 4:293–302
Kim YJ, Sapp E, Cuiffo BG, Sobin L, Yoder J, Kegel KB, DiFiglia M (2006) Lysosomal proteases are involved in generation of N-terminal huntingtin fragments. Neurobiol Dis 22:346–356
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 AβPP containing the wild-type β-secretase site sequence. J Alzheimers Dis 29:827–840
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
McGlinchey RP, Lee JC (2015) Cysteine cathepsins are essential in lysosomal degradation of α-synuclein. Proc Natl Acad Sci U S A 112:9322–9327
Moors T, Paciotti S, Chiasserini D, Calabresi P, Parnetti L, Beccari T, van de Berg WD (2016) Lysosomal dysfunction and α-Synuclein aggregation in Parkinson's disease: diagnostic links. Mov Disord 31:791–801
Ni H, Yan JZ, Zhang LL, Feng X, Wu XR (2012) Long-term effects of recurrent neonatal seizures on neurobehavioral function and related gene expression and its intervention by inhibitor of cathepsin B. Neurochem Res 37:31–39
Nixon RA (2013) The role of autophagy in neurodegenerative disease. Nat Med 19:983–997
Pišlar A, Kos J (2014) Cysteine cathepsins in neurological disorders. Mol Neurobiol 49:1017–1030
Reiser J, Adair B, Reinheckel T (2010) Specialized roles for cysteine cathepsins in health and disease. J Clin Invest 120:3421–3431
Smith KR, Dahl HH, Canafoglia L, Andermann E, Damiano J, Morbin M, Bahlo M (2013) Cathepsin F mutations cause type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis. Hum Mol Genet 22:1417–1423
Stoka V, Turk V, Turk B (2016) Lysosomal cathepsins and their regulation in aging and neurodegeneration. Ageing Res Rev 32:22–37
Sunkin SM, Ng L, Lau C, Dolbeare T, Gilbert TL, Thompson CL, Dang C (2013) Allen Brain Atlas: an integrated spatio-temporal portal for exploring the central nervous system. Nucleic Acids Res 41:D996–D1008
Talukdar R, Sareen A, Zhu H, Yuan Z, Dixit A, Cheema H, Saluja AK (2016) Release of cathepsin B in cytosol causes cell death in acute pancreatitis. Gastroenterology 151:747–758.e5
Yamashima T (2016) Can ‘calpain-cathepsin hypothesis’ explain Alzheimer neuronal death? Ageing Res. Rev 32:169–179
Zhou X, Paushter DH, Feng T, Sun L, Reinheckel T, Hu F (2017) Lysosomal processing of progranulin. Mol Neurodegener 12:62
Acknowledgements
We thank the Allen Human brain Atlas for providing the extensive efforts and gene expression data as a public resource (http://www.brain-map.org/).
Funding
This work was supported by a grant from the National Institutes of Health (NIH) (R01 NS094597) awarded to V. Hook. A. Hsu was supported by a NIH/NIA grant t32 AG26757 (Dilip V. Jeste, PI), and the Stein Institute for Research on Aging and the Center for Healthy Aging at the University of California, San Diego.
Author information
Authors and Affiliations
Corresponding author
Electronic Supplementary Material
ESM 1
Fig. S1. Human Brian Regions Evaluated for Cathepsin Gene Expression. Cathepsin protease expression was assessed in sixteen brain regions shown in panels (a) to (p). The tissue regions are (a) amyloid complex, (b) anterior cingulate cortex, (c) cerebellar cortex, (d) dorsolateral prefrontal cortex, (e) hippocampus, (f) interolateral termporal cortex, (g) mediodorsal nucleus of thalamus, (h) orbital frontal cortex, (i) primary motor cortex, (m) primary somatoensory cortex, (n) primary visual cortex, (o) striatum, and (p) ventrolateral prefrontal cortex. Fig. S2. Cathepsin L Gene Expression in Human Brain During Young to Adult Ages. Gene expression levels of cathepsin L are illustrated for the sixteen brain regions, panels (a) to (p), during six age periods of (1) early prenatal, (2) late prenatal, (3) infancy, (4) childhood, (5) adolescence, and (6) young adult. Bars show the average RPKM ± s.e.m. for each cathepsin, with statistical significance of (*p < 0.05, **p < 0.01, and ***p < 0.001) assessed by Kruskal-Wallis non-parametric t-test followed by Dunn’s multiple comparison post hoc test. Fig. S3. Cathepsin Z Gene Expression in Human Brain During Young to Adult Ages. Gene expression levels of cathepsin Z are illustrated for the sixteen brain regions, panels (a) to (p), during six age periods of (1) early prenatal, (2) late prenatal, (3) infancy, (4) childhood, (5) adolescence, and (6) young adult. Bars show the average RPKM ± s.e.m. for each cathepsin, with statistical significance of (*p < 0.05, **p < 0.01, and ***p < 0.001) assessed by Kruskal-Wallis non-parametric t-test followed by Dunn’s multiple comparison post hoc test. Fig. S4. Cathepsin A Gene Expression in Human Brain During Young to Adult Ages. Gene expression levels of cathepsin A are illustrated for the sixteen brain regions, panels (a) to (p), during six age periods of (1) early prenatal, (2) late prenatal, (3) infancy, (4) childhood, (5) adolescence, and (6) young adult. Bars show the average RPKM ± s.e.m. for each cathepsin, with statistical significance of (*p < 0.05, **p < 0.01, and ***p < 0.001) assessed by Kruskal-Wallis non-parametric t-test followed by Dunn’s multiple comparison post hoc test. Fig. S5. Cathepsin H Gene Expression in Human Brain During Young to Adult Ages. Gene expression levels of cathepsin H are illustrated for the sixteen brain regions, panels (a) to (p), during six age periods of (1) early prenatal, (2) late prenatal, (3) infancy, (4) childhood, (5) adolescence, and (6) young adult. Bars show the average RPKM ± s.e.m. for each cathepsin, with statistical significance of (*p < 0.05, **p < 0.01, and ***p < 0.001) assessed by Kruskal-Wallis non-parametric t-test followed by Dunn’s multiple comparison post hoc test. Fig. S6. Cathepsin O Gene Expression in Human Brain During Young to Adult Ages. Gene expression levels of cathepsin O are illustrated for the sixteen brain regions, panels (a) to (p), during six age periods of (1) early prenatal, (2) late prenatal, (3) infancy, (4) childhood, (5) adolescence, and (6) young adult. Bars show the average RPKM ± s.e.m. for each cathepsin, with statistical significance of (*p < 0.05, **p < 0.01, and ***p < 0.001) assessed by Kruskal-Wallis non-parametric t-test followed by Dunn’s multiple comparison post hoc test. (PDF 19185 kb)
ESM 2
(PDF 247 kb)
Rights and permissions
About this article
Cite this article
Hsu, A., Podvin, S. & Hook, V. Lysosomal Cathepsin Protease Gene Expression Profiles in the Human Brain During Normal Development. J Mol Neurosci 65, 420–431 (2018). https://doi.org/10.1007/s12031-018-1110-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-018-1110-6