Missense mutations in the progranulin gene linked to frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions reduce progranulin production and secretion - PubMed (original) (raw)
. 2008 Jan 18;283(3):1744-1753.
doi: 10.1074/jbc.M705115200. Epub 2007 Nov 5.
Affiliations
- PMID: 17984093
- DOI: 10.1074/jbc.M705115200
Free article
Missense mutations in the progranulin gene linked to frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions reduce progranulin production and secretion
Sunita S Shankaran et al. J Biol Chem. 2008.
Free article
Abstract
Loss of function mutations in progranulin cause tau-negative frontotemporal lobar degeneration with ubiquitin-positive inclusions. A major protein component of these inclusions is TDP-43, which becomes hyperphosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments, which apparently translocate from nuclei to the cytoplasm. Most progranulin mutations are nonsense mutations resulting in nonsense-mediated mRNA decay and consequently reduced progranulin protein levels. However, some missense mutations are described that occur within the signal sequence and mature progranulin. We now demonstrate that a progranulin mutation located within the signal sequence (PGRN A9D) results in cytoplasmic missorting with extremely low expression. In contrast, two other progranulin mutations (PGRN P248L and R432C) are expressed as immature proteins but are inefficiently transported through and partially degraded within the secretory pathway, resulting in a significantly reduced secretion. Thus apparently all progranulin mutations cause reduced protein expression or secretion, although by different cellular mechanisms. To investigate a putative relationship between reduced expression of progranulin and TDP-43 relocalization and deposition, we down-regulated progranulin in human cell lines and in zebrafish. Upon reduction of progranulin, neither a major redistribution of TDP-43 nor proteolytic processing to disease-characterizing C-terminal fragments could be observed.
Similar articles
- [Frontotemporal dementia (FTD) and genetic mutations including progranulin gene].
Arai T, Hasegawa M, Nishihara M, Nonaka T, Kametani F, Yoshida M, Hashizume Y, Beach TG, Morita M, Nakano I, Oda T, Tsuchiya K, Akiyama H. Arai T, et al. Rinsho Shinkeigaku. 2008 Nov;48(11):990-3. doi: 10.5692/clinicalneurol.48.990. Rinsho Shinkeigaku. 2008. PMID: 19198141 Review. Japanese. - Suppression of Progranulin Expression Leads to Formation of Intranuclear TDP-43 Inclusions In Vitro: A Cell Model of Frontotemporal Lobar Degeneration.
Zhu J, Wang N, Li X, Zheng X, Zhao J, Xia H, Mao Q. Zhu J, et al. J Neuropathol Exp Neurol. 2019 Dec 1;78(12):1124-1129. doi: 10.1093/jnen/nlz102. J Neuropathol Exp Neurol. 2019. PMID: 31626287 - HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin.
Mukherjee O, Pastor P, Cairns NJ, Chakraverty S, Kauwe JS, Shears S, Behrens MI, Budde J, Hinrichs AL, Norton J, Levitch D, Taylor-Reinwald L, Gitcho M, Tu PH, Tenenholz Grinberg L, Liscic RM, Armendariz J, Morris JC, Goate AM. Mukherjee O, et al. Ann Neurol. 2006 Sep;60(3):314-22. doi: 10.1002/ana.20963. Ann Neurol. 2006. PMID: 16983685 Free PMC article. - Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations.
Josephs KA, Ahmed Z, Katsuse O, Parisi JF, Boeve BF, Knopman DS, Petersen RC, Davies P, Duara R, Graff-Radford NR, Uitti RJ, Rademakers R, Adamson J, Baker M, Hutton ML, Dickson DW. Josephs KA, et al. J Neuropathol Exp Neurol. 2007 Feb;66(2):142-51. doi: 10.1097/nen.0b013e31803020cf. J Neuropathol Exp Neurol. 2007. PMID: 17278999 - Progranulin mutations in ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.
Cruts M, Kumar-Singh S, Van Broeckhoven C. Cruts M, et al. Curr Alzheimer Res. 2006 Dec;3(5):485-91. doi: 10.2174/156720506779025251. Curr Alzheimer Res. 2006. PMID: 17168647 Review.
Cited by
- Progranulin and GPNMB: interactions in endo-lysosome function and inflammation in neurodegenerative disease.
Gillett DA, Wallings RL, Uriarte Huarte O, Tansey MG. Gillett DA, et al. J Neuroinflammation. 2023 Nov 30;20(1):286. doi: 10.1186/s12974-023-02965-w. J Neuroinflammation. 2023. PMID: 38037070 Free PMC article. Review. - Frontotemporal-TDP and LATE Neurocognitive Disorders: A Pathophysiological and Genetic Approach.
Ortiz GG, Ramírez-Jirano J, Arizaga RL, Delgado-Lara DLC, Torres-Sánchez ED. Ortiz GG, et al. Brain Sci. 2023 Oct 18;13(10):1474. doi: 10.3390/brainsci13101474. Brain Sci. 2023. PMID: 37891841 Free PMC article. Review. - Regulation of extracellular progranulin in medial prefrontal cortex.
Kaplelach AK, Fox SN, Cook AK, Hall JA, Dannemiller RS, Jaunarajs KL, Arrant AE. Kaplelach AK, et al. Neurobiol Dis. 2023 Nov;188:106326. doi: 10.1016/j.nbd.2023.106326. Epub 2023 Oct 12. Neurobiol Dis. 2023. PMID: 37838007 Free PMC article. - The Role of Progranulin (PGRN) in the Pathogenesis of Ischemic Stroke.
Purrahman D, Shojaeian A, Poniatowski ŁA, Piechowski-Jóźwiak B, Mahmoudian-Sani MR. Purrahman D, et al. Cell Mol Neurobiol. 2023 Oct;43(7):3435-3447. doi: 10.1007/s10571-023-01396-8. Epub 2023 Aug 10. Cell Mol Neurobiol. 2023. PMID: 37561339 Review. - Contributions of rare and common variation to early-onset and atypical dementia risk.
Wright CA, Taylor JW, Cochran M, Lawlor JMJ, Moyers BA, Amaral MD, Bonnstetter ZT, Carter P, Solomon V, Myers RM, Love MN, Geldmacher DS, Cooper SJ, Roberson ED, Cochran JN. Wright CA, et al. Cold Spring Harb Mol Case Stud. 2023 Jul 11;9(3):a006271. doi: 10.1101/mcs.a006271. Print 2023 Jun. Cold Spring Harb Mol Case Stud. 2023. PMID: 37308299 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Miscellaneous