title: Common pathobiochemical hallmarks of progranulin-associated frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis.
abstract: Heterozygous loss-of-function mutations in the progranulin (GRN) gene and the resulting reduction of GRN levels is a common genetic cause for frontotemporal lobar degeneration (FTLD) with accumulation of TAR DNA-binding protein (TDP)-43. Recently, it has been shown that a complete GRN deficiency due to a homozygous GRN loss-of-function mutation causes neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder. These findings suggest that lysosomal dysfunction may also contribute to some extent to FTLD. Indeed, Grn(-/-) mice recapitulate not only pathobiochemical features of GRN-associated FTLD-TDP (FTLD-TDP/GRN), but also those which are characteristic for NCL and lysosomal impairment. In Grn(-/-) mice the lysosomal proteins cathepsin D (CTSD), LAMP (lysosomal-associated membrane protein) 1 and the NCL storage components saposin D and subunit c of mitochondrial ATP synthase (SCMAS) were all found to be elevated. Moreover, these mice display increased levels of transmembrane protein (TMEM) 106B, a lysosomal protein known as a risk factor for FTLD-TDP pathology. In line with a potential pathological overlap of FTLD and NCL, Ctsd(-/-) mice, a model for NCL, show elevated levels of the FTLD-associated proteins GRN and TMEM106B. In addition, pathologically phosphorylated TDP-43 occurs in Ctsd(-/-) mice to a similar extent as in Grn(-/-) mice. Consistent with these findings, some NCL patients accumulate pathologically phosphorylated TDP-43 within their brains. Based on these observations, we searched for pathological marker proteins, which are characteristic for NCL or lysosomal impairment in brains of FTLD-TDP/GRN patients. Strikingly, saposin D, SCMAS as well as the lysosomal proteins CTSD and LAMP1/2 are all elevated in patients with FTLD-TDP/GRN. Thus, our findings suggest that lysosomal storage disorders and GRN-associated FTLD may share common features.
authors.affiliation: Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians-University Munich, Schillerstrasse 44, 80336, Munich, Germany.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Götzl
authors.forename: Kohji
authors.initials: K
authors.lastname: Mori
authors.forename: Markus
authors.initials: M
authors.lastname: Damme
authors.forename: Katrin
authors.initials: K
authors.lastname: Fellerer
authors.forename: Sabina
authors.initials: S
authors.lastname: Tahirovic
authors.forename: Gernot
authors.initials: G
authors.lastname: Kleinberger
authors.forename: Jonathan
authors.initials: J
authors.lastname: Janssens
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.forename: Christina M
authors.initials: CM
authors.lastname: Lang
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Martin
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kretzschmar
authors.forename: Thomas
authors.initials: T
authors.lastname: Arzberger
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.forename: Anja
authors.initials: A
authors.lastname: Capell
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002402:Cathepsin D / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism* / Q000473:pathology*; D000077155:Granulins; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D009472:Neuronal Ceroid-Lipofuscinoses / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D000077153:Progranulins
chemical_list: D002402:Cathepsin D; D004268:DNA-Binding Proteins; D000077155:Granulins; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; C492314:GRN protein, human; C120204:Grn protein, mouse; C000598624:TARDBP protein, human; C578077:Tardbp protein, mouse; C533923:Ctsd protein, mouse