Alternative titles; symbols
HGNC Approved Gene Symbol: NPEPPS
Cytogenetic location: 17q21.32 Genomic coordinates (GRCh38) : 17:47,522,933-47,623,276 (from NCBI)
Aminopeptidases are a group of exopeptidases that hydrolyze amino acids from the N terminus of a peptide substrate. Puromycin-sensitive aminopeptidase (EC 3.4.11.14) contains the zinc-binding domain characteristic of the gluzincin group of zinc metalloproteases (see 605896).
Tobler et al. (1997) cloned PSA from a human fetal brain cDNA library using the mouse PSA cDNA as probe. They established that translation is initiated at the second of 2 possible start codons, resulting in a deduced 875-amino acid protein with a molecular mass of 99 kD by SDS-PAGE. PSA contains a zinc-binding motif conserved among gluzincin aminopeptidases and shares 98% sequence identity with the mouse protein. Northern blot analysis detected ubiquitous expression of a 4.8-kb transcript, with highest expression in brain. By in situ hybridization of adult human brain sections, expression was localized to the perikaryon of neurons of the cortex and cerebellum. Using immunofluorescence localization of transfected HeLa cells, Tobler et al. (1997) found that PSA localizes to the perinuclear cytoplasm and shows a filamentous staining pattern. Bauer et al. (2001) cloned PSA cDNA from a human skeletal muscle library. Northern blot analysis detected major and minor transcripts of 4.8 and 4.2 kb, respectively. Huber et al. (1999) determined that PSA is identical to the metalloprotease MP100 that was originally isolated as a beta-secretase candidate from human brain by Schonlein et al. (1994).
Huber et al. (1999) were able to colocalize and coimmunoprecipitate PSA with beta-amyloid precursor protein (104760); however, PSA did not increase production of the amyloid-beta peptide in cotransfected cells. By RT-PCR, but not by Northern blot analysis, Bauer et al. (2001) found that PSA was upregulated in human leukemic cells following vitamin D stimulation.
PSA is the only cytosolic enzyme able to digest polyQ sequences. Menzies et al. (2010) tested whether PSA could protect against accumulation of polyQ fragments. In cultured cells, Drosophila and mouse muscles, PSA inhibition or knockdown increased aggregate content and toxicity of polyQ-expanded huntingtin (HTT; 613004) exon 1. Conversely, PSA overexpression decreased aggregate content and toxicity. PSA inhibition also increased the levels of polyQ-expanded ataxin-3 (ATXN3; 607047) as well as mutant alpha-synuclein (SNCA; 163890) and superoxide dismutase-1 (SOD1; 147450). These protective effects result from an unexpected ability of PSA to enhance macroautophagy. PSA overexpression increased, and PSA knockdown or inhibition reduced, microtubule-associated protein-1 light chain-3-II (see MAP1LC3A, 601242) levels and the amount of protein degradation sensitive to inhibitors of lysosomal function and autophagy. Thus, by promoting autophagic protein clearance, PSA helps protect against accumulation of aggregation-prone proteins and proteotoxicity.
Thompson et al. (1999) determined that the PSA gene contains 23 exons spanning approximately 40 kb. They found that the active site motif iis split between exons 9 and 10. Analysis of the 5-prime flanking region indicated that the gene lacks a TATA box, is GC rich, and contains 5 putative SP1 (189906)-binding sites.
By FISH, Bauer et al. (2001) mapped the PSA gene to chromosome 17q21. Osada et al. (1999) mapped the mouse Psa gene to a region of syntenic homology on chromosome 11.
By analyzing short-read mapping depth for 159 human genomes, Sudmant et al. (2010) demonstrated accurate estimation of absolute copy number for duplications as small as 1.9 kb pairs, ranging from 0 to 48 copies. Sudmant et al. (2010) identified 4.1 million 'singly unique nucleotide' positions informative in distinguishing specific copies and used them to genotype the copy and content of specific paralogs within highly duplicated gene families. These data identified human-specific expansions in genes associated with brain development, such as GPRIN2 (611240) and SRGAP2 (606524), which have been implicated in neurite outgrowth and branching. Also included were the brain-specific HYDIN2 gene (610813), associated with micro- and macrocephaly; DRD5 (126453), a dopamine D5 receptor; and the GTF2I (601679) transcription factors, whose deletion has been associated with visual-spatial and sociability deficits among Williams-Beuren syndrome (194050) patients, among others. The data of Sudmant et al. (2010) also revealed extensive population genetic diversity, especially among the genes NPEPPS, UGT2B17 (601903), and NBPF1 (610501), as well as LILRA3 (604818), which is the most highly stratified gene by copy number in the human genome. In addition, Sudmant et al. (2010) detected signatures consistent with gene conversion in the human species.
Karsten et al. (2006) identified the Npepps gene as a tau (MAPT; 157140) modifier by using a cross-species functional genomic approach to analyze gene expression in mice. Npepps expression was increased in multiple brain regions in a mouse model of frontotemporal dementia (FTD; 600274) compared to control mice. In Drosophila, Npepps protected against tau-induced neurodegeneration, whereas loss of Npepps exacerbated neurodegeneration. Immunoblot, SDS-PAGE, and Western blot analyses showed that human NPEPPS directly proteolyzed and significantly diminished human tau. Western blot analysis of 6 brains derived from human FTD patients showed increased NPEPPS expression, particularly in the cerebellum.
Bauer, W. O., Nanda, I., Beck, G., Schmid, M., Jakob, F. Human puromycin-sensitive aminopeptidase: cloning of 3-prime UTR, evidence for a polymorphism at aa 140 and refined chromosomal localization to 17q21. Cytogenet. Cell Genet. 92: 221-224, 2001. [PubMed: 11435692] [Full Text: https://doi.org/10.1159/000056907]
Huber, G., Thompson, A., Gruninger, F., Mechler, H., Hochstrasser, R., Hauri, H.-P., Malherbe, P. cDNA cloning and molecular characterization of human brain metalloprotease MP100: a beta-secretase candidate? J. Neurochem. 72: 1215-1223, 1999. [PubMed: 10037494] [Full Text: https://doi.org/10.1046/j.1471-4159.1999.0721215.x]
Karsten, S. L., Sang, T.-K., Gehman, L. T., Chatterjee, S., Liu, J., Lawless, G. M., Sengupta, S., Berry, R. W., Pomakian, J., Oh, H. S., Schulz, C., Hui, K.-S., Wiedau-Pazos, M., Vinters, H. V., Binder, L. I., Geschwind, D. H., Jackson, G. R. A genomic screen for modifiers of tauopathy identified puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration. Neuron 51: 549-560, 2006. [PubMed: 16950154] [Full Text: https://doi.org/10.1016/j.neuron.2006.07.019]
Menzies, F. M., Hourez, R., Imarisio, S., Raspe, M., Sadiq, O., Chandraratna, D., O'Kane, C., Rock, K. L., Reits, E., Goldberg, A. L., Rubinsztein, D. C. Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy. Hum. Molec. Genet. 19: 4573-4586, 2010. [PubMed: 20829225] [Full Text: https://doi.org/10.1093/hmg/ddq385]
Osada, T., Sakaki, Y., Takeuchi, T. Puromycin-sensitive aminopeptidase gene (Psa) maps to mouse chromosome 11. Genomics 56: 361-362, 1999. [PubMed: 10087210] [Full Text: https://doi.org/10.1006/geno.1998.5724]
Schonlein, C., Loffler, J., Huber, G. Purification and characterization of a novel metalloprotease from human brain with the ability to cleave substrates derived from the N-terminus of beta-amyloid protein. Biochem. Biophys. Res. Commun. 201: 45-53, 1994. [PubMed: 8198608] [Full Text: https://doi.org/10.1006/bbrc.1994.1667]
Sudmant, P. H., Kitzman, J. O., Antonacci, F., Alkan, C., Malig, M., Tsalenko, A., Sampas, N., Bruhn, L., Shendure, J., 1000 Genomes Project, Eichler, E. E. Diversity of human copy number variation and multicopy genes. Science 330: 641-646, 2010. [PubMed: 21030649] [Full Text: https://doi.org/10.1126/science.1197005]
Thompson, M. W., Tobler, A., Fontana, A., Hersh, L. B. Cloning and analysis of the gene for the human puromycin-sensitive aminopeptidase. Biochem. Biophys. Res. Commun. 258: 234-240, 1999. [PubMed: 10329370] [Full Text: https://doi.org/10.1006/bbrc.1999.0604]
Tobler, A. R., Constam, D. B., Schmitt-Graff, A., Malipiero, U., Schlapbach, R., Fontana, A. Cloning of the human puromycin-sensitive aminopeptidase and evidence for expression in neurons. J. Neurochem. 68: 889-897, 1997. [PubMed: 9048733] [Full Text: https://doi.org/10.1046/j.1471-4159.1997.68030889.x]