| Autor: |
Gotzl, J., Colombo, Alessio Vittorio, Mazaheri, Fargol, Smith, S., Fellerer, K., Butovsky, O., Tahirovic, Sabina, Capell, A., Haass, Christian |
| Jazyk: |
angličtina |
| Rok vydání: |
2016 |
| Předmět: |
|
| Zdroj: |
Journal of neurochemistry 138(Supplement 1), 410 (2016). |
| Popis: |
Heterozygous loss-of-function mutations in the progranulin(GRN) gene result in GRN haploinsufficiency, which is a majorcause for familial frontotemporal lobar degeneration (FTLD) withTAR DNA-binding protein (TDP) -43 and ubiquitin-positiveinclusions. Homozygous loss-of-function mutations in GRN leadto an adult variant of neuronal ceroid lipofuscinosis (NCL), which isassociated with severe neurodegeneration. Brains of Grn knockoutmice show some features of FTLD pathology such as pathologicalphosphorylation of TDP-43, but also an age dependent increase oflysosomal proteins and an accumulation of lipofuscin indicatinglysosomal dysfunction. We showed previously (G€otzl et al., ActaNeuropathol. 2014, 127(6):845-60) that the levels of the lysosomalmembrane protein TMEM106B, a risk factor for FTLD-TDPassociated with GRN mutations, are increased among other lysoso-mal proteins such as cathepsin D, the transmembrane proteinLAMP1, and saposin D, a disease signifying storage component inNCL patients. The accumulation of lysosomal proteins in Grnknockout mice and two GRN NCL cases suggests that GRN mayplay a crucial role in the integrity and function of lysosomes in braintissue. We have now investigated, which cells in the brain contributeto the observed increase of lysosomal proteins in brains of Grnknockout mice. While LAMP1 is selectively increased in microgliacells, saposin D accumulated in a cell type-independent manner.Microglia cells are the main source of GRN in the brain, thus cellautonomous effects would be expected. To identify potentialchanges in microglia function and activity, we compared theirhomeostatic RNA signature in the presence and absence of GRN.Our data suggest that glial and neuronal cells differently contributeto the lysosomal phenotype in Grn knockout mice brains. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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