Publications by authors named "Julia K Götzl"

4 Publications

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Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism.

EMBO Mol Med 2019 06;11(6)

Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

Microglia adopt numerous fates with homeostatic microglia (HM) and a microglial neurodegenerative phenotype (MGnD) representing two opposite ends. A number of variants in genes selectively expressed in microglia are associated with an increased risk for neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Among these genes are progranulin () and the triggering receptor expressed on myeloid cells 2 (). Both cause neurodegeneration by mechanisms involving loss of function. We have now isolated microglia from mice and compared their transcriptomes to those of Surprisingly, while loss of enhances the expression of genes associated with a homeostatic state, microglia derived from mice showed a reciprocal activation of the MGnD molecular signature and suppression of gene characteristic for HM The opposite mRNA expression profiles are associated with divergent functional phenotypes. Although loss of TREM2 and progranulin resulted in opposite activation states and functional phenotypes of microglia, FDG (fluoro-2-deoxy-d-glucose)-μPET of brain revealed reduced glucose metabolism in both conditions, suggesting that opposite microglial phenotypes result in similar wide spread brain dysfunction.
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http://dx.doi.org/10.15252/emmm.201809711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554672PMC
June 2019

Early lysosomal maturation deficits in microglia triggers enhanced lysosomal activity in other brain cells of progranulin knockout mice.

Mol Neurodegener 2018 09 4;13(1):48. Epub 2018 Sep 4.

Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, 81377, Munich, Germany.

Background: Heterozygous loss-of-function mutations in the progranulin gene (GRN) lead to frontotemporal lobar degeneration (FTLD) while the complete loss of progranulin (PGRN) function results in neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Thus the growth factor-like protein PGRN may play an important role in lysosomal degradation. In line with a potential lysosomal function, PGRN is partially localized and processed in lysosomes. In the central nervous system (CNS), PGRN is like other lysosomal proteins highly expressed in microglia, further supporting an important role in protein degradation. We have previously reported that cathepsin (Cat) D is elevated in GRN-associated FTLD patients and Grn knockout mice. However, the primary mechanism that causes impaired protein degradation and elevated CatD levels upon PGRN deficiency in NCL and FTLD remains unclear.

Methods: mRNA expression analysis of selected lysosomal hydrolases, lysosomal membrane proteins and autophagy-related genes was performed by NanoString nCounter panel. Protein expression, maturation and in vitro activity of Cat D, B and L in mouse embryonic fibroblasts (MEF) and brains of Grn knockout mice were investigated. To selectively characterize microglial and non-microglial brain cells, an acutely isolated microglia fraction using MACS microbeads (Miltenyi Biotec) conjugated with CD11b antibody and a microglia-depleted fraction were analyzed for protein expression and maturation of selected cathepsins.

Results: We demonstrate that loss of PGRN results in enhanced expression, maturation and in vitro activity of Cat D, B and L in mouse embryonic fibroblasts and brain extracts of aged Grn knockout mice. Consistent with an overall enhanced expression and activity of lysosomal proteases in brain of Grn knockout mice, we observed an age-dependent transcriptional upregulation of certain lysosomal proteases. Thus, lysosomal dysfunction is not reflected by transcriptional downregulation of lysosomal proteases but rather by the upregulation of certain lysosomal proteases in an age-dependent manner. Surprisingly, cell specific analyses identified early lysosomal deficits in microglia before enhanced cathepsin levels could be detected in other brain cells, suggesting different functional consequences on lysosomal homeostasis in microglia and other brain cells upon lack of PGRN.

Conclusions: The present study uncovers early and selective lysosomal dysfunctions in Grn knockout microglia/macrophages. Dysregulated lysosomal homeostasis in microglia might trigger compensatory lysosomal changes in other brain cells.
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http://dx.doi.org/10.1186/s13024-018-0281-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123925PMC
September 2018

Impaired protein degradation in FTLD and related disorders.

Ageing Res Rev 2016 12 7;32:122-139. Epub 2016 May 7.

Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University, Munich, Germany. Electronic address:

Impaired protein degradation has been discussed as a cause or consequence of various neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's disease. More recently, evidence accumulated that dysfunctional protein degradation may play a role in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Since in almost all neurodegenerative diseases, protein aggregates are disease-defining hallmarks, it is most likely that impaired protein degradation contributes to disease onset and progression. In the majority of FTD cases, the pathological protein aggregates contain either microtubuleassociated protein tau or TAR DNA-binding protein (TDP)-43. Aggregates are also positive for ubiquitin and p62/sequestosome 1 (SQSTM1) indicating that these aggregates are targeted for degradation. FTD-linked mutations in genes encoding three autophagy adaptor proteins, p62/SQSTM1, ubiquilin 2 and optineurin, indicate that impaired autophagy might cause FTD. Furthermore, the strongest evidence for lysosomal impairment in FTD is provided by the progranulin (GRN) gene, which is linked to FTD and neuronal ceroid lipofuscinosis. In this review, we summarize the observations that have been made during the last years linking the accumulation of disease-associated proteins in FTD to impaired protein degradation pathways. In addition, we take resent findings for nucleocytoplasmic transport defects of TDP-43, as discussed for hexanucleotide repeat expansions in C9orf72 into account and provide a hypothesis how the interplay of altered nuclear transport and protein degradation leads to the accumulation of protein deposits.
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http://dx.doi.org/10.1016/j.arr.2016.04.008DOI Listing
December 2016

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

Acta Neuropathol 2014 12;127(6):845-60. Epub 2014 Mar 12.

Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians-University Munich, Schillerstrasse 44, 80336, Munich, Germany.

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.
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http://dx.doi.org/10.1007/s00401-014-1262-6DOI Listing
August 2015