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000157806 041__ $$aEnglish
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000157806 1001_ $$0P:(DE-2719)2812186$$aLerche, Stefanie$$b0$$eFirst author$$udzne
000157806 245__ $$aThe Mutation Matters: CSF Profiles of GCase, Sphingolipids, α-Synuclein in PDGBA.
000157806 260__ $$aNew York, NY$$bWiley$$c2021
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000157806 520__ $$aWith pathway-specific trials in PD associated with variants in the glucocerebrosidase gene (PDGBA ) under way, we need markers that confirm the impact of genetic variants in patient-derived biofluids in order to allow patient stratification merely based on genetics and that might serve as biochemical read-out for target engagement.To explore GBA-pathway-specific biomarker profiles cross-sectionally (TUEPAC-MIGAP, PPMI) and longitudinally (PPMI).We measured enzyme activity of the lysosomal glucocerebrosidase, CSF levels of glucosylceramides (upstream substrate of glucocerebrosidase), CSF levels of ceramides (downstream product of glucocerebrosidase), lactosylceramides, sphingosines, sphingomyelin (by-products) and CSF levels of total α-synuclein in PDGBA patients compared to PDGBA_wildtype patients.Cross-sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PDGBA compared to PDGBA_wildtype . (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PDGBA compared to PDGBA_wildtype . (3) CSF levels of total α-synuclein were lower in PDGBA compared to PDGBA_wildtype . All of these findings were most pronounced in PDGBA with severe mutations (PDGBA_severe ). Cross-sectionally in TUEPAC-MIGAP and longitudinally in PPMI, CSF levels of downstream-products (ceramides) were higher in PDGBA_severe . Cross-sectionally in TUEPAC-MIGAP by-products sphinganine and sphingosine-1-phosphate and longitudinally in PPMI species of by-products lactosylceramides and sphingomyelin were higher in PDGBA_severe .These findings confirm that GBA mutations have a relevant functional impact on biomarker profiles in patients. Bridging the gap between genetics and biochemical profiles now allows patient stratification for clinical trials merely based on mutation status. Importantly, all findings were most prominent in PDGBA with severe variants. © 2021 International Parkinson and Movement Disorder Society.
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000157806 650_7 $$2Other$$aCSF
000157806 650_7 $$2Other$$aGBA
000157806 650_7 $$2Other$$aGCase
000157806 650_7 $$2Other$$aceramides
000157806 650_7 $$2Other$$aα-synuclein
000157806 650_7 $$2NLM Chemicals$$aSphingolipids
000157806 650_7 $$2NLM Chemicals$$aalpha-Synuclein
000157806 650_7 $$0EC 3.2.1.45$$2NLM Chemicals$$aGlucosylceramidase
000157806 650_2 $$2MeSH$$aGlucosylceramidase: genetics
000157806 650_2 $$2MeSH$$aHumans
000157806 650_2 $$2MeSH$$aMutation: genetics
000157806 650_2 $$2MeSH$$aParkinson Disease: genetics
000157806 650_2 $$2MeSH$$aSphingolipids
000157806 650_2 $$2MeSH$$aalpha-Synuclein: genetics
000157806 7001_ $$0P:(DE-2719)9000366$$aSchulte, Claudia$$b1$$udzne
000157806 7001_ $$0P:(DE-2719)2812736$$aWurster, Isabel$$b2$$udzne
000157806 7001_ $$0P:(DE-2719)9000193$$aMachetanz, Gerrit$$b3$$udzne
000157806 7001_ $$0P:(DE-2719)2811830$$aRoeben, Benjamin$$b4$$udzne
000157806 7001_ $$0P:(DE-2719)9000951$$aZimmermann, Milan$$b5$$udzne
000157806 7001_ $$0P:(DE-2719)2812432$$aDeuschle, Christian$$b6$$udzne
000157806 7001_ $$0P:(DE-2719)2351249$$aHauser, Ann-Kathrin$$b7$$udzne
000157806 7001_ $$aBöhringer, Judith$$b8
000157806 7001_ $$0P:(DE-2719)9000936$$aKragelöh-Mann, Ingeborg$$b9$$udzne
000157806 7001_ $$aWaniek, Katharina$$b10
000157806 7001_ $$aLachmann, Ingolf$$b11
000157806 7001_ $$aPetterson, Xuan-Mai T$$b12
000157806 7001_ $$aChiang, Ruby$$b13
000157806 7001_ $$aPark, Hyejung$$b14
000157806 7001_ $$aWang, Bing$$b15
000157806 7001_ $$0P:(DE-2719)2109499$$aLiepelt-Scarfone, Inga$$b16$$udzne
000157806 7001_ $$0P:(DE-2719)2810915$$aMaetzler, Walter$$b17$$udzne
000157806 7001_ $$aGalasko, Douglas$$b18
000157806 7001_ $$aScherzer, Clemens R$$b19
000157806 7001_ $$0P:(DE-2719)2320009$$aGasser, Thomas$$b20$$udzne
000157806 7001_ $$aMielke, Michelle M$$b21
000157806 7001_ $$aHutten, Samantha J$$b22
000157806 7001_ $$0P:(DE-2719)9001340$$aMollenhauer, Brit$$b23$$udzne
000157806 7001_ $$aSardi, S Pablo$$b24
000157806 7001_ $$0P:(DE-2719)2000059$$aBerg, Daniela$$b25$$udzne
000157806 7001_ $$0P:(DE-2719)2811916$$aBrockmann, Kathrin$$b26$$eLast author$$udzne
000157806 773__ $$0PERI:(DE-600)2041249-6$$a10.1002/mds.28472$$gVol. 36, no. 5, p. 1216 - 1228$$n5$$p1216 - 1228$$tMovement disorders$$v36$$x1531-8257$$y2021
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