Common pathobiochemical hallmarks of progranulin-associated frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis

• Published in: Acta neuropathologica 2014-06, Vol.127 (6), p.845-860
• Main Authors: Götzl, Julia K., Mori, Kohji, Damme, Markus, Fellerer, Katrin, Tahirovic, Sabina, Kleinberger, Gernot, Janssens, Jonathan, van der Zee, Julie, Lang, Christina M., Kremmer, Elisabeth, Martin, Jean-Jacques, Engelborghs, Sebastiaan, Kretzschmar, Hans A., Arzberger, Thomas, Van Broeckhoven, Christine, Haass, Christian, Capell, Anja
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Animals; Biochemistry; Brain - metabolism; Brain - pathology; Cathepsin D - genetics; Cathepsin D - metabolism; Cathepsins; Dementia; Disease; Disease Models, Animal; DNA; DNA-Binding Proteins - metabolism; Frontotemporal Lobar Degeneration - metabolism; Frontotemporal Lobar Degeneration - pathology; Humans; Immunoblotting; Immunohistochemistry; Intercellular Signaling Peptides and Proteins - deficiency; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Medicine; Medicine & Public Health; Mice, Knockout; Mutation; Neurodegeneration; Neuronal Ceroid-Lipofuscinoses - metabolism; Neuronal Ceroid-Lipofuscinoses - pathology; Neurons; Neurosciences; Original Paper; Pathology; Phosphorylation; Protein binding; Proteins
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-014-1262-6

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.