FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3091987029> ?p ?o ?g. }

• W3091987029 abstract "Abstract Heterozygous, loss-of-function mutations in the granulin gene ( GRN ) encoding progranulin (PGRN) are a common cause of frontotemporal dementia (FTD). Homozygous GRN mutations cause neuronal ceroid lipofuscinosis-11 (CLN11), a lysosome storage disease. PGRN is a secreted glycoprotein that can be proteolytically cleaved into seven bioactive 6 kDa granulins. However, it is unclear how deficiency of PGRN and granulins causes neurodegeneration. To gain insight into the mechanisms of FTD pathogenesis, we utilized Tandem Mass Tag isobaric labeling mass spectrometry to perform an unbiased quantitative proteomic analysis of whole-brain tissue from wild type ( Grn +/+ ) and Grn knockout ( Grn −/− ) mice at 3- and 19-months of age. At 3-months lysosomal proteins (i.e. Gns, Scarb2, Hexb) are selectively increased indicating lysosomal dysfunction is an early consequence of PGRN deficiency. Additionally, proteins involved in lipid metabolism (Acly, Apoc3, Asah1, Gpld1, Ppt1, and Naaa) are decreased; suggesting lysosomal degradation of lipids may be impaired in the Grn −/− brain. Systems biology using weighted correlation network analysis (WGCNA) of the Grn −/− brain proteome identified 26 modules of highly co-expressed proteins. Three modules strongly correlated to Grn deficiency and were enriched with lysosomal proteins (Gpnmb, CtsD, CtsZ, and Tpp1) and inflammatory proteins (Lgals3, GFAP, CD44, S100a, and C1qa). We find that lysosomal dysregulation is exacerbated with age in the Grn −/− mouse brain leading to neuroinflammation, synaptic loss, and decreased markers of oligodendrocytes, myelin, and neurons. In particular, GPNMB and LGALS3 (galectin-3) were upregulated by microglia and elevated in FTD- GRN brain samples, indicating common pathogenic pathways are dysregulated in human FTD cases and Grn −/− mice. GPNMB levels were significantly increased in the cerebrospinal fluid of FTD- GRN patients, but not in MAPT or C9orf72 carriers, suggesting GPNMB could be a biomarker specific to FTD- GRN to monitor disease onset, progression, and drug response. Our findings support the idea that insufficiency of PGRN and granulins in humans causes neurodegeneration through lysosomal dysfunction, defects in autophagy, and neuroinflammation, which could be targeted to develop effective therapies." @default.
• W3091987029 created "2020-10-15" @default.
• W3091987029 creator A5005318820 @default.
• W3091987029 creator A5005417427 @default.
• W3091987029 creator A5009533777 @default.
• W3091987029 creator A5016701884 @default.
• W3091987029 creator A5022349887 @default.
• W3091987029 creator A5040892881 @default.
• W3091987029 creator A5051844354 @default.
• W3091987029 creator A5059359131 @default.
• W3091987029 creator A5061526409 @default.
• W3091987029 creator A5063529297 @default.
• W3091987029 creator A5075035041 @default.
• W3091987029 creator A5076978362 @default.
• W3091987029 date "2020-10-07" @default.
• W3091987029 modified "2023-10-16" @default.
• W3091987029 title "Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations" @default.
• W3091987029 cites W1483210419 @default.
• W3091987029 cites W1559233041 @default.
• W3091987029 cites W1690143157 @default.
• W3091987029 cites W1861730929 @default.
• W3091987029 cites W1894766672 @default.
• W3091987029 cites W1955394435 @default.
• W3091987029 cites W1964226422 @default.
• W3091987029 cites W1966327575 @default.
• W3091987029 cites W1970055334 @default.
• W3091987029 cites W1972638185 @default.
• W3091987029 cites W1973522156 @default.
• W3091987029 cites W1975200363 @default.
• W3091987029 cites W1979315191 @default.
• W3091987029 cites W1986554546 @default.
• W3091987029 cites W1992138269 @default.
• W3091987029 cites W1995793646 @default.
• W3091987029 cites W1999639946 @default.
• W3091987029 cites W2001811842 @default.
• W3091987029 cites W2003618511 @default.
• W3091987029 cites W2004128782 @default.
• W3091987029 cites W2005731595 @default.
• W3091987029 cites W2007157687 @default.
• W3091987029 cites W2012157443 @default.
• W3091987029 cites W2027460468 @default.
• W3091987029 cites W2029235884 @default.
• W3091987029 cites W2034183549 @default.
• W3091987029 cites W2039756269 @default.
• W3091987029 cites W2041981154 @default.
• W3091987029 cites W2044940518 @default.
• W3091987029 cites W2045921574 @default.
• W3091987029 cites W2046700952 @default.
• W3091987029 cites W2056607803 @default.
• W3091987029 cites W2064797576 @default.
• W3091987029 cites W2068037486 @default.
• W3091987029 cites W2070063785 @default.
• W3091987029 cites W2070161555 @default.
• W3091987029 cites W2077499130 @default.
• W3091987029 cites W2081837126 @default.
• W3091987029 cites W2084343282 @default.
• W3091987029 cites W2098246435 @default.
• W3091987029 cites W2103029879 @default.
• W3091987029 cites W2106248056 @default.
• W3091987029 cites W2113556948 @default.
• W3091987029 cites W2117026326 @default.
• W3091987029 cites W2125044837 @default.
• W3091987029 cites W2133254377 @default.
• W3091987029 cites W2134318672 @default.
• W3091987029 cites W2136057227 @default.
• W3091987029 cites W2140447941 @default.
• W3091987029 cites W2150715552 @default.
• W3091987029 cites W2156054547 @default.
• W3091987029 cites W2156512271 @default.
• W3091987029 cites W2158198121 @default.
• W3091987029 cites W2164687616 @default.
• W3091987029 cites W2167792273 @default.
• W3091987029 cites W2210071362 @default.
• W3091987029 cites W2269555972 @default.
• W3091987029 cites W2288574569 @default.
• W3091987029 cites W2307542306 @default.
• W3091987029 cites W2341088037 @default.
• W3091987029 cites W2346657977 @default.
• W3091987029 cites W239648239 @default.
• W3091987029 cites W2396748779 @default.
• W3091987029 cites W2471306658 @default.
• W3091987029 cites W2487820682 @default.
• W3091987029 cites W2489093230 @default.
• W3091987029 cites W2558669106 @default.
• W3091987029 cites W2563754444 @default.
• W3091987029 cites W2567533903 @default.
• W3091987029 cites W2567618101 @default.
• W3091987029 cites W2606944807 @default.
• W3091987029 cites W2607714873 @default.
• W3091987029 cites W2607906243 @default.
• W3091987029 cites W2613333544 @default.
• W3091987029 cites W2615732360 @default.
• W3091987029 cites W2619755571 @default.
• W3091987029 cites W2736651324 @default.
• W3091987029 cites W2742515342 @default.
• W3091987029 cites W2746890128 @default.
• W3091987029 cites W2749058695 @default.
• W3091987029 cites W2752326209 @default.
• W3091987029 cites W2752806811 @default.
• W3091987029 cites W2754890392 @default.

• next