PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer's disease.
PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer's disease.
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DOI：
10.1371/journal.pgen.1009406
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发表时间：
2021-04
期刊：
影响因子：
4.5
通讯作者：
Schrag MS
中科院分区：
文献类型：
--
作者：
Nackenoff AG;Hohman TJ;Neuner SM;Akers CS;Weitzel NC;Shostak A;Ferguson SM;Mobley B;Bennett DA;Schneider JA;Jefferson AL;Kaczorowski CC;Schrag MS
磷脂酶D3（PLD 3）是一种功能不清楚的蛋白质，其结构类似于磷脂酶D超家族的其他成员。该基因中的编码变体赋予阿尔茨海默病（AD）发展的风险增加，尽管这种影响的程度一直存在争议。由于这种模糊的蛋白质的潜在意义，我们进行了一项研究，以观察其在正常人脑和AD影响的大脑中的分布，确定PLD 3是否与记忆和认知在散发性AD，并评估其分子功能。在人类神经病理学样品中，PLD 3主要在神经元内发现，并与溶酶体标志物（LAMP 2、颗粒蛋白前体和组织蛋白酶D和B）共定位。这种共定位也存在于AD脑中，在β-淀粉样蛋白斑块周围的营养不良神经突内的溶酶体积累上显著富集。这种蛋白质分布模式在野生型小鼠脑和脑淀粉样变性的5xFAD小鼠模型中是保守的。我们发现PLD 3在溶酶体中具有磷脂酶D活性。与野生型PLD 3相比，报告赋予AD风险的PLD 3中的编码变体显著降低了酶活性。在宗教秩序研究和拉什记忆和衰老项目的531名参与者中，人类前额叶皮层中的PLD 3 mRNA水平与β淀粉样蛋白病理严重程度和认知下降率呈负相关。遗传多样性BXD小鼠品系和与5xFAD小鼠杂交的品系中的PLD 3水平与恐惧条件反射任务中的学习和记忆表现强烈相关。总之，本研究鉴定了一种新的功能性哺乳动物磷脂酶D同种型，其为溶酶体型并且与β-淀粉样蛋白病理学和认知密切相关。磷酸脂酶D3（PLD 3）的一种罕见变异与阿尔茨海默病（AD）风险有关，但该变异对蛋白质功能的影响以及PLD 3在散发性AD中的作用尚不清楚。在这里，我们表明，PLD 3是一种溶酶体磷脂酶D和AD相关的变体损害其功能。我们还发现，PLD 3表达水平与β-淀粉样蛋白斑块密度和纵向宗教秩序研究和拉什记忆和衰老项目中的认知下降率相关。最后，我们在遗传多样性小鼠模型中观察到PLD 3表达水平与记忆和学习相关。这些发现证实了PLD 3是一个重要的AD风险基因，并暗示PLD 3在AD中的溶酶体功能障碍的神经生物学中。
Phospholipase D3 (PLD3) is a protein of unclear function that structurally resembles other members of the phospholipase D superfamily. A coding variant in this gene confers increased risk for the development of Alzheimer’s disease (AD), although the magnitude of this effect has been controversial. Because of the potential significance of this obscure protein, we undertook a study to observe its distribution in normal human brain and AD-affected brain, determine whether PLD3 is relevant to memory and cognition in sporadic AD, and to evaluate its molecular function. In human neuropathological samples, PLD3 was primarily found within neurons and colocalized with lysosome markers (LAMP2, progranulin, and cathepsins D and B). This colocalization was also present in AD brain with prominent enrichment on lysosomal accumulations within dystrophic neurites surrounding β-amyloid plaques. This pattern of protein distribution was conserved in mouse brain in wild type and the 5xFAD mouse model of cerebral β-amyloidosis. We discovered PLD3 has phospholipase D activity in lysosomes. A coding variant in PLD3 reported to confer AD risk significantly reduced enzymatic activity compared to wild-type PLD3. PLD3 mRNA levels in the human pre-frontal cortex inversely correlated with β-amyloid pathology severity and rate of cognitive decline in 531 participants enrolled in the Religious Orders Study and Rush Memory and Aging Project. PLD3 levels across genetically diverse BXD mouse strains and strains crossed with 5xFAD mice correlated strongly with learning and memory performance in a fear conditioning task. In summary, this study identified a new functional mammalian phospholipase D isoform which is lysosomal and closely associated with both β-amyloid pathology and cognition. A rare variant in phosphlipase D3 (PLD3) was linked to Alzheimer’s disease (AD) risk, but both the impact of the variant on protein’s function and the role of PLD3 in sporadic AD are unknown. Here we show that PLD3 is a lysosomal phospholipase D and that the AD-associated variant impairs its function. We also discovered that PLD3 expression levels correlate β-amyloid plaque density and the rate of cognitive decline in the longitudinal Religious Orders Study and Rush Memory and Aging Project. Finally, we observed PLD3 expression levels correlated with memory and learning in a genetically diverse mouse model. These discoveries establish that PLD3 is an important AD risk gene and implicate PLD3 in the neurobiology of lysosomal dysfunction in AD.
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DOI：
10.3233/jad-179939
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Bennett DA;Buchman AS;Boyle PA;Barnes LL;Wilson RS;Schneider JA
通讯作者：
Schneider JA
影响因子：
30.5
作者：
Gavin AL;Huang D;Huber C;Mårtensson A;Tardif V;Skog PD;Blane TR;Thinnes TC;Osborn K;Chong HS;Kargaran F;Kimm P;Zeitjian A;Sielski RL;Briggs M;Schulz SR;Zarpellon A;Cravatt B;Pang ES;Teijaro J;de la Torre JC;O'Keeffe M;Hochrein H;Damme M;Teyton L;Lawson BR;Nemazee D
通讯作者：
Nemazee D
DOI：
10.1038/nrn.2017.36
发表时间：
2017-06
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Kao AW;McKay A;Singh PP;Brunet A;Huang EJ
通讯作者：
Huang EJ
DOI：
10.1038/nrd.2016.252
发表时间：
2017-05
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Brown HA;Thomas PG;Lindsley CW
通讯作者：
Lindsley CW
影响因子：
3.5
作者：
Diettrich, O;Mills, K;Winchester, BG
通讯作者：
Winchester, BG