Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson's disease.
Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson's disease.
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DOI：
10.1038/s41531-023-00517-w
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发表时间：
2023-05-11
影响因子：
8.7
通讯作者：
Henderson, Michael X.
中科院分区：
文献类型：
--
作者：
Leyns, Cheryl E. G.;Prigent, Alice;Beezhold, Brenna;Yao, Lihang;Hatcher, Nathan G.;Tao, Peining;Kang, John;Suh, EunRan;Van Deerlin, Vivianna M.;Trojanowski, John Q.;Lee, Virginia M. Y.;Kennedy, Matthew E.;Fell, Matthew J.;Henderson, Michael X.
帕金森病（PD）和路易体痴呆（DLB）是以路易病理学形式的错误折叠的α-突触核蛋白积累为特征的进行性神经退行性疾病。虽然大多数病例是散发性的，但也有罕见的基因突变会导致疾病，而更常见的变异会增加疾病的发病率。PD和DLB最突出的基因突变在GBA 1和LRRK 2基因中。GBA 1突变与葡萄糖脑苷脂酶活性降低及其脂质底物葡萄糖神经酰胺和葡萄糖鞘氨醇的溶酶体蓄积相关。以前的研究表明，即使在散发性PD中，这种酶与脂质之间也存在联系。然而，目前尚不清楚疾病的蛋白质病理学如何与酶活性和鞘糖脂水平相关。为了解决这一知识缺口，我们平行检查了91例无神经系统疾病、特发性、GBA 1相关或LRRK 2相关PD和DLB的大脑4个区域的定量蛋白质病理学、葡萄糖脑苷脂酶活性和脂质底物。我们发现，几个生物标志物的变化与突变和进展为痴呆症。我们发现葡萄糖脑苷脂酶活性与疾病有轻度相关性，但葡萄糖鞘氨醇与α-突触核蛋白病理学有强烈相关性，与基因突变无关。这种关联表明，路易病理沉淀的脂质水平的变化与进展为痴呆症。
Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases characterized by the accumulation of misfolded α-synuclein in the form of Lewy pathology. While most cases are sporadic, there are rare genetic mutations that cause disease and more common variants that increase incidence of disease. The most prominent genetic mutations for PD and DLB are in the GBA1 and LRRK2 genes. GBA1 mutations are associated with decreased glucocerebrosidase activity and lysosomal accumulation of its lipid substrates, glucosylceramide and glucosylsphingosine. Previous studies have shown a link between this enzyme and lipids even in sporadic PD. However, it is unclear how the protein pathologies of disease are related to enzyme activity and glycosphingolipid levels. To address this gap in knowledge, we examined quantitative protein pathology, glucocerebrosidase activity and lipid substrates in parallel from 4 regions of 91 brains with no neurological disease, idiopathic, GBA1-linked, or LRRK2-linked PD and DLB. We find that several biomarkers are altered with respect to mutation and progression to dementia. We found mild association of glucocerebrosidase activity with disease, but a strong association of glucosylsphingosine with α-synuclein pathology, irrespective of genetic mutation. This association suggests that Lewy pathology precipitates changes in lipid levels related to progression to dementia.
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影响因子：
12.7
作者：
Kurzawa-Akanbi M;Tammireddy S;Fabrik I;Gliaudelytė L;Doherty MK;Heap R;Matečko-Burmann I;Burmann BM;Trost M;Lucocq JM;Gherman AV;Fairfoul G;Singh P;Burté F;Green A;McKeith IG;Härtlova A;Whitfield PD;Morris CM
通讯作者：
Morris CM
影响因子：
48
作者：
Irwin, David;Grossman, Murray;Weintraub, Daniel;Hurtig, Howard I.;Duda, John E.;Xie, Sharon X.;Lee, Edward B.;Van Deerlin, Vivianna M.;Lopez, Oscar L.;Kofler, Julia K.;Nelson, Peter T.;Jicha, Gregory A.;Woltjer, Randy;Quinn, Joseph F.;Kaye, Jeffery;Leverenz, James B.;Tsuang, Debby;Longfellow, Katelan;Yearout, Dora;Kukull, Walter;Keene, C. Dirk;Montine, Thomas J.;Zabetian, Cyrus P.;Trojanowski, John Q.
通讯作者：
Trojanowski, John Q.
影响因子：
7.4
作者：
Boutin, Michel;Sun, Ying;Auray-Blais, Christiane
通讯作者：
Auray-Blais, Christiane
影响因子：
9.9
作者：
Anheim, M.;Elbaz, A.;Brice, A.
通讯作者：
Brice, A.
影响因子：
16.2
作者：
Aflaki E;Westbroek W;Sidransky E
通讯作者：
Sidransky E