PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer's disease.

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 controversi...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Alex G Nackenoff, Timothy J Hohman, Sarah M Neuner, Carolyn S Akers, Nicole C Weitzel, Alena Shostak, Shawn M Ferguson, Bret Mobley, David A Bennett, Julie A Schneider, Angela L Jefferson, Catherine C Kaczorowski, Matthew S Schrag
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/5332a5a2c04747fa938b639208224775
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5332a5a2c04747fa938b639208224775
record_format	dspace
spelling	oai:doaj.org-article:5332a5a2c04747fa938b6392082247752021-12-02T20:02:47ZPLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer's disease.1553-73901553-740410.1371/journal.pgen.1009406https://doaj.org/article/5332a5a2c04747fa938b6392082247752021-04-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009406https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Phospholipase 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.Alex G NackenoffTimothy J HohmanSarah M NeunerCarolyn S AkersNicole C WeitzelAlena ShostakShawn M FergusonBret MobleyDavid A BennettJulie A SchneiderAngela L JeffersonCatherine C KaczorowskiMatthew S SchragPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 4, p e1009406 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Alex G Nackenoff Timothy J Hohman Sarah M Neuner Carolyn S Akers Nicole C Weitzel Alena Shostak Shawn M Ferguson Bret Mobley David A Bennett Julie A Schneider Angela L Jefferson Catherine C Kaczorowski Matthew S Schrag PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer's disease.
description	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.
format	article
author	Alex G Nackenoff Timothy J Hohman Sarah M Neuner Carolyn S Akers Nicole C Weitzel Alena Shostak Shawn M Ferguson Bret Mobley David A Bennett Julie A Schneider Angela L Jefferson Catherine C Kaczorowski Matthew S Schrag
author_facet	Alex G Nackenoff Timothy J Hohman Sarah M Neuner Carolyn S Akers Nicole C Weitzel Alena Shostak Shawn M Ferguson Bret Mobley David A Bennett Julie A Schneider Angela L Jefferson Catherine C Kaczorowski Matthew S Schrag
author_sort	Alex G Nackenoff
title	PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer's disease.
title_short	PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer's disease.
title_full	PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer's disease.
title_fullStr	PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer's disease.
title_full_unstemmed	PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer's disease.
title_sort	pld3 is a neuronal lysosomal phospholipase d associated with β-amyloid plaques and cognitive function in alzheimer's disease.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/5332a5a2c04747fa938b639208224775
work_keys_str_mv	AT alexgnackenoff pld3isaneuronallysosomalphospholipasedassociatedwithbamyloidplaquesandcognitivefunctioninalzheimersdisease AT timothyjhohman pld3isaneuronallysosomalphospholipasedassociatedwithbamyloidplaquesandcognitivefunctioninalzheimersdisease AT sarahmneuner pld3isaneuronallysosomalphospholipasedassociatedwithbamyloidplaquesandcognitivefunctioninalzheimersdisease AT carolynsakers pld3isaneuronallysosomalphospholipasedassociatedwithbamyloidplaquesandcognitivefunctioninalzheimersdisease AT nicolecweitzel pld3isaneuronallysosomalphospholipasedassociatedwithbamyloidplaquesandcognitivefunctioninalzheimersdisease AT alenashostak pld3isaneuronallysosomalphospholipasedassociatedwithbamyloidplaquesandcognitivefunctioninalzheimersdisease AT shawnmferguson pld3isaneuronallysosomalphospholipasedassociatedwithbamyloidplaquesandcognitivefunctioninalzheimersdisease AT bretmobley pld3isaneuronallysosomalphospholipasedassociatedwithbamyloidplaquesandcognitivefunctioninalzheimersdisease AT davidabennett pld3isaneuronallysosomalphospholipasedassociatedwithbamyloidplaquesandcognitivefunctioninalzheimersdisease AT julieaschneider pld3isaneuronallysosomalphospholipasedassociatedwithbamyloidplaquesandcognitivefunctioninalzheimersdisease AT angelaljefferson pld3isaneuronallysosomalphospholipasedassociatedwithbamyloidplaquesandcognitivefunctioninalzheimersdisease AT catherineckaczorowski pld3isaneuronallysosomalphospholipasedassociatedwithbamyloidplaquesandcognitivefunctioninalzheimersdisease AT matthewsschrag pld3isaneuronallysosomalphospholipasedassociatedwithbamyloidplaquesandcognitivefunctioninalzheimersdisease
_version_	1718375659681611776

PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer's disease.

Ejemplares similares