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Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency.

ABSTRACT: Defective lysosomal function defines many neurodegenerative diseases, such as neuronal ceroid lipofuscinoses (NCL) and Niemann-Pick type C (NPC), and is implicated in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD-TDP) with progranulin (PGRN) deficiency. Here, we show that PGRN is involved in lysosomal homeostasis and lipid metabolism. PGRN deficiency alters lysosome abundance and morphology in mouse neurons. Using an unbiased lipidomic approach, we found that brain lipid composition in humans and mice with PGRN deficiency shows disease-specific differences that distinguish them from normal and other pathologic groups. PGRN loss leads to an accumulation of polyunsaturated triacylglycerides, as well as a reduction of diacylglycerides and phosphatidylserines in fibroblast and enriched lysosome lipidomes. Transcriptomic analysis of PGRN-deficient mouse brains revealed distinct expression patterns of lysosomal, immune-related, and lipid metabolic genes. These findings have implications for the pathogenesis of FTLD-TDP due to PGRN deficiency and suggest lysosomal dysfunction as an underlying mechanism.

SUBMITTER: Evers BM

PROVIDER: S-EPMC5757843 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency.

Evers Bret M BM Rodriguez-Navas Carlos C Tesla Rachel J RJ Prange-Kiel Janine J Wasser Catherine R CR Yoo Kyoung Shin KS McDonald Jeffrey J Cenik Basar B Ravenscroft Thomas A TA Plattner Florian F Rademakers Rosa R Yu Gang G White Charles L CL Herz Joachim J

Cell reports 20170901 11

Defective lysosomal function defines many neurodegenerative diseases, such as neuronal ceroid lipofuscinoses (NCL) and Niemann-Pick type C (NPC), and is implicated in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD-TDP) with progranulin (PGRN) deficiency. Here, we show that PGRN is involved in lysosomal homeostasis and lipid metabolism. PGRN deficiency alters lysosome abundance and morphology in mouse neurons. Using an unbiased lipidomic approach, we found that brain lipid c ...[more]

PMID: 28903038

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Project description:BackgroundFrontotemporal lobar degeneration (FTLD) is a devastating and progressive disorder, and a common cause of early onset dementia. Progranulin (PGRN) haploinsufficiency due to autosomal dominant mutations in the progranulin gene (GRN) is an important cause of FTLD (FTLD-GRN), and nearly a quarter of these genetic cases are due to a nonsense mutation. Premature termination codons (PTC) can be therapeutically targeted by compounds allowing readthrough, and aminoglycoside antibiotics are known to be potent PTC readthrough drugs. Restoring endogenous PGRN through PTC readthrough has not previously been explored as a therapeutic intervention in FTLD.MethodsWe studied whether the aminoglycoside G418 could increase PGRN expression in HEK293 and human induced pluripotent stem cell (hiPSC)-derived neurons bearing the heterozygous S116X, R418X, and R493X pathogenic GRN nonsense mutations. We further tested a novel substituted phthalimide PTC readthrough enhancer in combination with G418 in our cellular models. We next generated a homozygous R493X knock-in hiPSC isogenic line (R493X-/- KI), assessing whether combination treatment in hiPSC-derived neurons and astrocytes could increase PGRN and ameliorate lysosomal dysfunction relevant to FTLD-GRN. To provide in vivo proof-of-concept of our approach, we measured brain PGRN after intracerebroventricular administration of G418 in mice expressing the V5-tagged GRN nonsense mutation R493X.ResultsThe R418X and R493X mutant GRN cell lines responded to PTC readthrough with G418, and treatments increased PGRN levels in R493X-/- KI hiPSC-derived neurons and astrocytes. Combining G418 with a PTC readthrough enhancer increased PGRN levels over G418 treatment alone in vitro. PGRN deficiency has been shown to impair lysosomal function, and the mature form of the lysosomal protease cathepsin D is overexpressed in R493X-/- KI neurons. Increasing PGRN through G418-mediated PTC readthrough normalized this abnormal lysosomal phenotype in R493X-/- KI neuronal cultures. A single intracerebroventricular injection of G418 induced GRN PTC readthrough in 6-week-old AAV-GRN-R493X-V5 mice.ConclusionsTaken together, our findings suggest that PTC readthrough may be a potential therapeutic strategy for FTLD caused by GRN nonsense mutations.

Project description:BackgroundAge-related macular degeneration (AMD) is the principal cause of permanent blindness among elderly individuals worldwide. Chronic inflammation in the subretinal space is associated with a progression of exudative AMD. Progranulin (PGRN) is a growth factor secreted from myeloid cells and plays an important role in controlling the lysosomal function. A deficiency in PGRN leads to inflammation of the neurons in the central nervous system. The purpose of this study was to investigate the role played by PGRN in the size of the choroidal neovascularization (CNV) in laser-induced CNV mice.MethodsCNVs were induced in C57BL/6J mice by laser photocoagulation of the retina. The expression of PGRN and the accumulation of Iba-1+ cells around the sites of the CNVs were determined. Grn-/-, Grn+/-, and Grn+/+ mice with laser-induced CNVs were also studied. To evaluate the effect of macrophages on the inflammation, we used a macrophage cell line (RAW264.7) in which the expression of PGRN was knocked down by RNA interference and peritoneal macrophages derived from Grn-/- and Grn+/+ mice. These cells were incubated under hypoxic conditions (1% O2).ResultsIba-1+ myeloid cells migrated and accumulated in the photocoagulation-induced CNV areas, and the CNV lesions secreted high levels of PGRN in Grn+/+ mice. The size of the CNVs was larger in Grn-/- mice than in Grn+/- and Grn+/+ mice. In Grn-/- mice, the number of ocular-infiltrating Iba-1+ cells around the CNV was higher, and these cells produced more VEGF-A than the cells in the Grn+/+ mice. PGRN-silencing of RAW264.7 cells led to abnormal activation of the cells. In addition, hypoxic conditions promoted the production of proangiogenic and proinflammatory cytokines from PGRN-deficient macrophages. Interestingly, the expression level of lysosome-associated proteins and the number of activated lysosomes increased in PGRN-deficient macrophages.ConclusionsThese findings indicate that PGRN deficiency in Iba-1+ cells activates the lysosomal function that then leads to abnormal inflammation. The aberrant activation of Iba-1+ myeloid cells might contribute to the progression of the CNV and the regulation of these cells might be a novel therapeutic target for exudative AMD.

Dataset Information

Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency.

Publications

Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency.

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