Progranulin-derived granulin E and lysosome membrane protein CD68 interact to reciprocally regulate their protein homeostasis

Abstract

Progranulin (PGRN) is a glycoprotein implicated in several neurodegenerative diseases. It is highly expressed in microglia and macrophages and can be secreted or delivered to the lysosome compartment. PGRN comprises 7.5 granulin repeats and is processed into individual granulin peptides within the lysosome, but the functions of these peptides are largely unknown. Here, we identify CD68, a lysosome membrane protein mainly expressed in hematopoietic cells, as a binding partner of PGRN and PGRN-derived granulin E. Deletion analysis of CD68 showed that this interaction is mediated by the mucin–proline-rich domain of CD68. While CD68 deficiency does not affect the lysosomal localization of PGRN, it results in a specific decrease in the levels of granulin E but no other granulin peptides. On the other hand, the deficiency of PGRN, and its derivative granulin peptides, leads to a significant shift in the molecular weight of CD68, without altering CD68 localization within the cell. Our results support that granulin E and CD68 reciprocally regulate each other’s protein homeostasis. Progranulin (PGRN) is a glycoprotein implicated in several neurodegenerative diseases. It is highly expressed in microglia and macrophages and can be secreted or delivered to the lysosome compartment. PGRN comprises 7.5 granulin repeats and is processed into individual granulin peptides within the lysosome, but the functions of these peptides are largely unknown. Here, we identify CD68, a lysosome membrane protein mainly expressed in hematopoietic cells, as a binding partner of PGRN and PGRN-derived granulin E. Deletion analysis of CD68 showed that this interaction is mediated by the mucin–proline-rich domain of CD68. While CD68 deficiency does not affect the lysosomal localization of PGRN, it results in a specific decrease in the levels of granulin E but no other granulin peptides. On the other hand, the deficiency of PGRN, and its derivative granulin peptides, leads to a significant shift in the molecular weight of CD68, without altering CD68 localization within the cell. Our results support that granulin E and CD68 reciprocally regulate each other’s protein homeostasis. Frontotemporal lobar degeneration is a progressive neurodegenerative disease characterized by changes in personality and behavior as well as cognitive decline and language impairments (https://www.uptodate.com/contents/frontotemporal-dementia-epidemiology-pathology-and-pathogenesis) (1Neary D. Snowden J.S. Gustafson L. Passant U. Stuss D. Black S. et al.Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria.Neurology. 1998; 51: 1546-1554Crossref PubMed Scopus (4546) Google Scholar, 2Rabinovici G.D. Miller Bruce L. Frontotemporal lobar degeneration.CNS Drugs. 2010; 24: 375-398Crossref PubMed Scopus (303) Google Scholar). Mutation in the granulin (GRN) gene, resulting in haploinsufficiency of the progranulin (PGRN) protein, is one of the leading causes of frontotemporal lobar degeneration (3Baker M. Mackenzie I.R. Pickering-Brown S.M. Gass J. Rademakers R. Lindholm C. et al.Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.Nature. 2006; 442: 916-919Crossref PubMed Scopus (1663) Google Scholar, 4Cruts M. Gijselinck I. van der Zee J. Engelborghs S. Wils H. Pirici D. et al.Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.Nature. 2006; 442: 920-924Crossref PubMed Scopus (1279) Google Scholar, 5Gass J. Cannon A. Mackenzie I.R. Boeve B. Baker M. Adamson J. et al.Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration.Hum. Mol. Genet. 2006; 15: 2988-3001Crossref PubMed Scopus (494) Google Scholar), with over 70 disease-associated GRN mutations identified (https://www.uptodate.com/contents/frontotemporal-dementia-epidemiology-pathology-and-pathogenesis). PGRN is a secreted glycoprotein that is involved in many cellular processes, including inflammation, wound healing, and tumorigenesis (6Bateman A. Bennett H.P. The granulin gene family: from cancer to dementia.Bioessays. 2009; 31: 1245-1254Crossref PubMed Scopus (277) Google Scholar, 7Cenik B. Sephton C.F. Kutluk Cenik B. Herz J. Yu G. Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration.J. Biol. Chem. 2012; 287: 32298-32306Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). PGRN is widely considered to be anti-inflammatory, aiding in the reduction of proinflammatory cytokines and reducing the activation of microglia and astrocytes (7Cenik B. Sephton C.F. Kutluk Cenik B. Herz J. Yu G. Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration.J. Biol. Chem. 2012; 287: 32298-32306Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, 8Kao A.W. McKay A. Singh P.P. Brunet A. Huang E.J. Progranulin, lysosomal regulation and neurodegenerative disease.Nat. Rev. Neurosci. 2017; 18: 325-333Crossref PubMed Scopus (148) Google Scholar, 9Nicholson A.M. Gass J. Petrucelli L. Rademakers R. Progranulin axis and recent developments in frontotemporal lobar degeneration.Alzheimers Res. Ther. 2012; 4: 4Crossref PubMed Scopus (19) Google Scholar). Structurally, PGRN is comprised of 7.5 granulin segments, denoted as granulin A, B, C, D, E, F, and G, and the half-granulin segment known as paragranulin (6Bateman A. Bennett H.P. The granulin gene family: from cancer to dementia.Bioessays. 2009; 31: 1245-1254Crossref PubMed Scopus (277) Google Scholar, 7Cenik B. Sephton C.F. Kutluk Cenik B. Herz J. Yu G. Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration.J. Biol. Chem. 2012; 287: 32298-32306Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). The granulin peptides have been shown to possess functions that are independent of PGRN (6Bateman A. Bennett H.P. The granulin gene family: from cancer to dementia.Bioessays. 2009; 31: 1245-1254Crossref PubMed Scopus (277) Google Scholar, 7Cenik B. Sephton C.F. Kutluk Cenik B. Herz J. Yu G. Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration.J. Biol. Chem. 2012; 287: 32298-32306Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, 8Kao A.W. McKay A. Singh P.P. Brunet A. Huang E.J. Progranulin, lysosomal regulation and neurodegenerative disease.Nat. Rev. Neurosci. 2017; 18: 325-333Crossref PubMed Scopus (148) Google Scholar). In addition, accumulating evidence supports that PGRN is critical for proper lysosomal function (8Kao A.W. McKay A. Singh P.P. Brunet A. Huang E.J. Progranulin, lysosomal regulation and neurodegenerative disease.Nat. Rev. Neurosci. 2017; 18: 325-333Crossref PubMed Scopus (148) Google Scholar, 10Paushter D.H. Du H. Feng T. Hu F. The lysosomal function of progranulin, a guardian against neurodegeneration.Acta Neuropathol. 2018; 136: 1-17Crossref PubMed Scopus (113) Google Scholar). Complete loss of PGRN, caused by homozygous mutations in the GRN gene, leads to neuronal ceroid lipofuscinosis, a lysosomal storage disorder that is characterized by degeneration of nerve cells and the accumulation of autofluorescent lipofuscin (11Almeida M.R. Macario M.C. Ramos L. Baldeiras I. Ribeiro M.H. Santana I. Portuguese family with the co-occurrence of frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis phenotypes due to progranulin gene mutation.Neurobiol. Aging. 2016; 41: 200.e1-200.e5Crossref PubMed Scopus (87) Google Scholar, 12Smith K.R. Damiano J. Franceschetti S. Carpenter S. Canafoglia L. Morbin M. et al.Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage.Am. J. Hum. Genet. 2012; 90: 1102-1107Abstract Full Text Full Text PDF PubMed Scopus (360) Google Scholar). PGRN is a resident lysosomal protein and trafficked to the lysosome via two independent pathways, directly by the sortilin receptor (13Hu F. Sortilin-mediated endocytosis determines levels of the fronto-temporal dementia protein.Progranulin. 2010; 68: 654-667Google Scholar) or indirectly by binding to the soluble lysosomal protein, prosaposin (PSAP), which carries PGRN with it to the lysosome when it binds its own trafficking receptors, low-density lipoprotein receptor–related protein 1 or the cation-independent mannose-6-phosphate receptor (14Zhou X. Sun L. de Oliveira F.B. Qi X. Brown W.J. Smolka M.B. et al.Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin.J. Cell Biol. 2015; 210: 991-1002Crossref PubMed Scopus (131) Google Scholar). Within the lysosome, PGRN is processed into individual granulin peptides by lysosomal proteases (15Holler C.J. Taylor G. Deng Q. Kukar T. Intracellular proteolysis of progranulin generates stable, lysosomal granulins that are haploinsufficient in patients with frontotemporal dementia caused by GRN mutations.eNeuro. 2017; 4https://doi.org/10.1523/ENEURO.0100-17.2017Crossref PubMed Scopus (83) Google Scholar, 16Lee C.W. Stankowski J.N. Chew J. Cook C.N. Lam Y.-W. Almeida S. et al.The lysosomal protein cathepsin L is a progranulin protease.Mol. Neurodegen. 2017; 12: 55Crossref PubMed Scopus (62) Google Scholar, 17Zhou X. Paushter D.H. Feng T. Sun L. Reinheckel T. Hu F. Lysosomal processing of progranulin.Mol. Neurodegen. 2017; 12: 62Crossref PubMed Scopus (49) Google Scholar, 18Mohan S. Sampognaro P.J. Argouarch A.R. Maynard J.C. Welch M. Patwardhan A. et al.Processing of progranulin into granulins involves multiple lysosomal proteases and is affected in frontotemporal lobar degeneration.Mol. Neurodegen. 2021; 16: 51Crossref PubMed Scopus (11) Google Scholar), and these granulin peptides have been proposed to be the functional units of PGRN to regulate lysosomal functions. In support of this, the activities of several lysosomal enzymes, including cathepsin D (19Beel S. Moisse M. Damme M. De Muynck L. Robberecht W. Van Den Bosch L. et al.Progranulin functions as a cathepsin D chaperone to stimulate axonal outgrowth in vivo.Hum. Mol. Genet. 2017; 26: 2850-2863Crossref PubMed Scopus (94) Google Scholar, 20Butler V.J. Cortopassi W.A. Argouarch A.R. Ivry S.L. Craik C.S. Jacobson M.P. et al.Progranulin stimulates the in vitro maturation of pro-cathepsin D at acidic pH.J. Mol. Biol. 2019; 431: 1038-1047Crossref PubMed Scopus (38) Google Scholar, 21Valdez C. Wong Y.C. Schwake M. Bu G. Wszolek Z.K. Krainc D. Progranulin-mediated deficiency of cathepsin D results in FTD and NCL-like phenotypes in neurons derived from FTD patients.Hum. Mol. Genet. 2017; 26: 4861-4872Crossref PubMed Scopus (80) Google Scholar, 22Zhou X. Paushter D.H. Feng T. Pardon C.M. Mendoza C.S. Hu F. Regulation of cathepsin D activity by the FTLD protein progranulin.Acta Neuropathol. 2017; 134: 151-153Crossref PubMed Scopus (50) Google Scholar), glucocerebrosidase (GCase) (23Zhou X. Paushter D.H. Pagan M.D. Kim D. Nunez Santos M. Lieberman R.L. et al.Progranulin deficiency leads to reduced glucocerebrosidase activity.PLoS One. 2019; 14e0212382Crossref Scopus (44) Google Scholar, 24Arrant A.E. Roth J.R. Boyle N.R. Kashyap S.N. Hoffmann M.Q. Murchison C.F. et al.Impaired activity and processing in frontotemporal dementia due to progranulin Neuropathol. 2019; PubMed Scopus Google Scholar, C. D. J. Krainc D. Progranulin mutations in processing of prosaposin and reduced glucocerebrosidase Mol. Genet. PubMed Scopus Google Scholar, T. A. A. et of a lysosomal storage disorder caused by loss of function with a progranulin 2021; Full Text Full Text PDF PubMed Scopus Google Scholar), and S. Sampognaro P.J. Argouarch A.R. Maynard J.C. Welch M. Patwardhan A. et al.Processing of progranulin into granulins involves multiple lysosomal proteases and is affected in frontotemporal lobar degeneration.Mol. Neurodegen. 2021; 16: 51Crossref PubMed Scopus (11) Google Scholar), have been shown to be affected by the loss of PGRN and granulin peptides. PGRN deficiency results in the accumulation of in which is by the reduction in cathepsin D levels W. J. M. S. et lysosome to and in 2021; Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, PGRN shown to with and PGRN loss leads to a significant reduction in levels T. A. A. et of a lysosomal storage disorder caused by loss of function with a progranulin 2021; Full Text Full Text PDF PubMed Scopus Google Scholar). the function of each granulin to be the levels of individual granulin peptides are derived from the T. Du H. Santos X. Pagan M.D. et regulation of progranulin derived granulin Neurodegen. PubMed Scopus Google Scholar), but the involved in the of individual granulins in the lysosome unknown. Here, we the of CD68 as a binding partner for PGRN and granulin E. CD68 is a protein that is expressed in microglia and macrophages and to the and lysosomal membrane M.C. not a 2017; 4Crossref PubMed Scopus Google Scholar). the function of CD68 to be support that CD68 and granulin E regulate each other’s in the identify of PGRN or granulin peptides, we the from the The into a a and into The cells with PGRN or granulin peptides. a M. Q. of or as in for of cells, and PubMed Scopus Google Scholar). this we identified the protein, CD68, as a binding partner for granulin E these we of CD68 with PGRN or granulin peptides and that CD68 binds to PGRN and granulin E but no other granulins Deletion of the of PGRN, which the granulin E domain the interaction with CD68 that CD68 binds to PGRN via the granulin E CD68 the the mucin–proline-rich and the membrane protein domain M.C. not a 2017; 4Crossref PubMed Scopus Google Scholar). which of CD68 the interaction with granulin E, we of CD68. Deletion of the mucin–proline-rich but not the CD68 binding to PGRN and granulin E A, and that the mucin–proline-rich domain of CD68 is for the interaction with PGRN and granulin E. CD68 is in the membrane and the lysosomal we that CD68 function as a PGRN lysosomal trafficking this, we CD68 into cells and the cells with the cells as a CD68 is to the of PGRN but we the lysosomal localization of PGRN in that PGRN with lysosomal cathepsin D and of macrophages and microglia in the CD68 can PGRN of CD68 does not have on PGRN lysosomal trafficking in in PGRN lysosomal trafficking to levels of PGRN in the as in the of sortilin or deficiency (13Hu F. Sortilin-mediated endocytosis determines levels of the fronto-temporal dementia protein.Progranulin. 2010; 68: 654-667Google Scholar, X. Sun L. de Oliveira F.B. Qi X. Brown W.J. Smolka M.B. et al.Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin.J. Cell Biol. 2015; 210: 991-1002Crossref PubMed Scopus (131) Google Scholar). CD68 a PGRN lysosomal trafficking we that CD68 deficiency PGRN lysosomal trafficking and cause in the levels of the levels of PGRN in the not in PGRN is processed to granulin peptides in the lysosome, and in PGRN trafficking to PGRN processing (15Holler C.J. Taylor G. Deng Q. Kukar T. Intracellular proteolysis of progranulin generates stable, lysosomal granulins that are haploinsufficient in patients with frontotemporal dementia caused by GRN mutations.eNeuro. 2017; 4https://doi.org/10.1523/ENEURO.0100-17.2017Crossref PubMed Scopus (83) Google Scholar). CD68 PGRN we determined the levels of granulin peptides in the CD68 is highly The levels of PGRN and granulin peptides are not in that CD68 is not PGRN lysosomal trafficking CD68 with granulin E and the granulin E domain of PGRN, we CD68 deficiency granulin E this, we against individual granulin peptides T. Du H. Santos X. Pagan M.D. et regulation of progranulin derived granulin Neurodegen. PubMed Scopus Google Scholar) and the levels of granulin E and other granulins in the from the and which have levels of CD68 against granulin A, B, C, E, and F, but not D and G, can granulin peptides T. Du H. Santos X. Pagan M.D. et regulation of progranulin derived granulin Neurodegen. PubMed Scopus Google Scholar). results that is a significant reduction in the levels of granulin E, but no other granulins in and and microglia from and The specific reduction of granulin E in be due to PGRN reduced of granulin E in the lysosome, or changes in granulin E or CD68 granulin E we cells with granulin E. that CD68 is to the endocytosis and lysosomal of granulin E when in cells that granulin E trafficking be affected by CD68. we to a for granulin E in the of or not that the of granulin E is and the decrease in granulin E levels in CD68 cells is of or CD68 deficiency leads to reduced levels of granulin E and granulin E been shown to regulate J. A. C.J. Progranulin as a chaperone and multiple lysosomal 2017; 4: PubMed Scopus Google Scholar) and cathepsin D activities (19Beel S. Moisse M. Damme M. De Muynck L. Robberecht W. Van Den Bosch L. et al.Progranulin functions as a cathepsin D chaperone to stimulate axonal outgrowth in vivo.Hum. Mol. Genet. 2017; 26: 2850-2863Crossref PubMed Scopus (94) Google Scholar, 21Valdez C. Wong Y.C. Schwake M. Bu G. Wszolek Z.K. Krainc D. Progranulin-mediated deficiency of cathepsin D results in FTD and NCL-like phenotypes in neurons derived from FTD patients.Hum. Mol. Genet. 2017; 26: 4861-4872Crossref PubMed Scopus (80) Google Scholar), we determined loss of CD68 affect and cathepsin D and and In addition, we the levels of and are by CD68 loss and with PGRN to the lysosome X. Sun L. et al.Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin 2017; Scopus Google Scholar), and the granulins D and E have a interaction with X. Sun L. Hu F. The interaction progranulin and prosaposin is mediated by granulins and the and C.J. 2017; PubMed Scopus Google Scholar). The levels of and are not by CD68 that CD68 does not affect or the deficiency of PGRN and granulin peptides affect CD68 protein we CD68 protein in cells and analysis of showed a decrease in the molecular weight of CD68 in to in CD68 levels changes of CD68 are in microglia and macrophages and CD68 is a resident lysosomal the shift be of changes in lysosomal or of CD68. the we the cells with and which are that the lysosomal and decrease lysosomal CD68 in cells is not by lysosome that CD68 changes are not of in are for the changes in CD68 to from CD68 from or The shift of CD68 is in the of that the of CD68 in is not due to in is that CD68 protein on the membrane be processed by proteases resulting in the changes in this, we and cells with and or of the CD68 in cells that the decrease in CD68 is not to be caused by processing of the we CD68 localization is by PGRN In and cells, CD68 to the lysosome as by the CD68 and the lysosomal cathepsin D CD68 is in the we the levels of CD68 at the are in this, we levels of CD68 in in and cells and that CD68 levels not in cells D and PGRN is processed into individual granulin peptides in the lysosome, and these granulin peptides are proposed to possess functions to regulate lysosomal activities (15Holler C.J. Taylor G. Deng Q. Kukar T. Intracellular proteolysis of progranulin generates stable, lysosomal granulins that are haploinsufficient in patients with frontotemporal dementia caused by GRN mutations.eNeuro. 2017; 4https://doi.org/10.1523/ENEURO.0100-17.2017Crossref PubMed Scopus (83) Google Scholar, D. S. A. et of progranulin with functional PubMed Scopus Google Scholar). the granulin peptides are derived from the recent have shown that the levels of individual granulin peptides from each other T. Du H. Santos X. Pagan M.D. et regulation of progranulin derived granulin Neurodegen. PubMed Scopus Google Scholar). is by that CD68 the levels of granulin E but no other granulins and CD68 the levels of granulin E to be we to granulins in the it is that CD68 the levels of granulin E via its or CD68 can the of granulin E to the lysosome when in cells we that CD68 is for the of granulin E in the lysosomal compartment. It is that each granulin with a different of lysosomal which the and of these peptides in the CD68 is not expressed in binding partner for granulin E in neurons and other to granulin E. CD68 is critical for proper levels of granulin E, we that granulin lysosomal activities be in we not have a of granulin E functions in the In the J. A. C.J. Progranulin as a chaperone and multiple lysosomal 2017; 4: PubMed Scopus Google Scholar) and cathepsin D (19Beel S. Moisse M. Damme M. De Muynck L. Robberecht W. Van Den Bosch L. et al.Progranulin functions as a cathepsin D chaperone to stimulate axonal outgrowth in vivo.Hum. Mol. Genet. 2017; 26: 2850-2863Crossref PubMed Scopus (94) Google Scholar, 21Valdez C. Wong Y.C. Schwake M. Bu G. Wszolek Z.K. Krainc D. Progranulin-mediated deficiency of cathepsin D results in FTD and NCL-like phenotypes in neurons derived from FTD patients.Hum. Mol. Genet. 2017; 26: 4861-4872Crossref PubMed Scopus (80) Google Scholar) have been shown to be by granulin E, but activities are not by CD68 and is to the functions of granulin E in the lysosome and the of CD68 on granulin lysosomal Our have shown that PGRN deficiency results in a shift in the of CD68 in to in CD68 levels and The shift is not caused by in or It is that loss of PGRN leads to in the of CD68, CD68 M.C. not a 2017; 4Crossref PubMed Scopus Google Scholar). is the function of CD68 is affected by PGRN CD68 is as a for macrophages and is known its molecular functions M.C. not a 2017; 4Crossref PubMed Scopus Google Scholar). CD68 and and low-density lipoprotein on the membrane have been but the of this interaction to be M.C. not a 2017; 4Crossref PubMed Scopus Google Scholar, M.P. D. Cell of and CD68 and as for U. S. A. PubMed Scopus Google Scholar, D. that the of lipoprotein a in its interaction with U. S. A. 1998; PubMed Scopus Google Scholar). of CD68 functions the of the shift in identified CD68 as a specific binding partner for granulin E and that regulation of CD68 be one function of granulin E in the The in this CD68 PGRN and and from a from and D a from Brown at against each granulin have been characterized T. Du H. Santos X. Pagan M.D. et regulation of progranulin derived granulin Neurodegen. PubMed Scopus Google Scholar). by and and characterized (14Zhou X. Sun L. de Oliveira F.B. Qi X. Brown W.J. Smolka M.B. et al.Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin.J. Cell Biol. 2015; 210: 991-1002Crossref PubMed Scopus (131) Google Scholar). from from and The in the and CD68 in the A, and the The to PGRN and granulins into the with the from the in the from and into the via L. C. C. Deletion of the receptor Res. Full Text Full Text PDF PubMed Scopus Google Scholar), and F. R. B. L. T. et inflammation, and in 2009; PubMed Scopus Google Scholar) from to in a and are in the have been by the and at with at a of 1 for of the of the The and by with a and and cells in with in a at with cells with PGRN or by the cells with and the and or with and the is by and cells with as A.R. S. M. M. of in as and 4: PubMed Scopus Google Scholar). from and to J. B. macrophages and PubMed Scopus Google Scholar). the cells from the and of and in with and with a and neurons and microglia from to to X. Sun L. et al.Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin 2017; Scopus Google Scholar, H. Wong T. Santos C. J. et of progranulin in and 2021; PubMed Scopus Google Scholar). cells in with to of for individual protein in each as a for PGRN and as a the with with and with and and with or a of A, B, D, E, and at protein to in to each and the for at the with to of and the cells with at for with and by the with and the with The at to with and and with of of with and at for a of or as by the of by in a at for at to on to which or and for to at on and to with in or for 1 at by with and at with with for and with for 1 at and by and of granulin and in 1 and 1 a membrane with in for at by with for and as with and and with and at On the of the and on with a in a of and with at for at determined via and of protein by the from and with and determined via and with at for by the of of with at for of each on a which at with a and as with to from and in and at at a of weight to of at for in 1 and in the of the The as a of cathepsin D activity at and from of to and at at for two and and PGRN with and as Huang M. Hu F. The frontotemporal lobar degeneration lysosomal and Mol. Genet. PubMed Scopus Google Scholar). cells on for with domain of or CD68 in with by in for at with and with with for 1 The of and the CD68 and CD68 from independent The analysis of the analysis of levels of the and the directly a and with in for by with and in with a The and with in by with and as from and and in and The at for at and the protein the The with of protein and in a for 1 at The at for at and the and in to which against CD68 and for to of protein and for at at for at and with 1 of a and for a of the of and into two and by the of of with the other to the the 1 of glycoprotein and to the The to for and on for of of and of and the 1 of and at for 1 of the and are as by or to considered and The the of this are from the on for the and of The is by the and at The that have no of with the of this T. F. and H. D. D. H. and S. M. B. T. M. D. H. T. X. J. S. M. R. H. and F. H. M. S. and F. H. D. H. T. and S. M. B. is by the of and on of and and the to frontotemporal dementia to F. H. The are not involved in the The is the of the and does not the of the of

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