PLD3 and spinocerebellar ataxia

Gonzalez, Adriana Carolina; Reisdorf, Pia; Gavin, Amanda L.; Nemazee, David; Schwudke, Dominik; D’Hooge, Rudi; Säftig, Paul; Damme, Markus

doi:10.1093/brain/awy258

Cited by 13 publications

(15 citation statements)

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“…Interestingly, the major coding variant V232M showed reduced activity in our experiments. A mutation in PLD3 has recently been linked to an autosomal dominant form of spinocerebellar ataxia ( 23 ), even though it remains questionable if the mutation in PLD3 is causative for the disease ( 17 ). The assay described here might be used as a suitable test for diagnosing this subtype of spinocerebellar ataxia.…”

Section: Discussionmentioning

confidence: 99%

“…Besides its role in the innate immune system, PLD3 previously received considerable attention, as genetic variants in PLD3 were shown to increase the risk of developing Alzheimer’s disease (AD) ( 15 ). It should be noted that PLD3 is highly expressed in the brain and, in particular, in cortical neurons ( 16 , 17 ). Particularly one coding variant (V232M) was shown to double the risk to develop the disease, and several other variants were exclusively found in AD patients but absent in nondemented control subjects ( 15 ).…”

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confidence: 99%

“…In addition to genetic variants in AD, a mutation in PLD3 was recently found to cause for a rare form of autosomal dominant spinocerebellar ataxia ( 23 ). As in the case of AD, this genetic association was also challenged because Pld3 knockout mice do not develop any signs of spinocerebellar ataxia ( 17 ).…”

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Quantification and characterization of the 5′ exonuclease activity of the lysosomal nuclease PLD3 by a novel cell-based assay

Cappel¹,

Gonzalez²,

Damme

2021

Journal of Biological Chemistry

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Phospholipase D3 (PLD3) and phospholipase D4 (PLD4), the most recently described lysosomal nucleases, are associated with Alzheimer’s disease, spinocerebellar ataxia, and systemic lupus erythematosus. They exhibit 5′ exonuclease activity on single-stranded DNA, hydrolyzing it at the acidic pH associated with the lysosome. However, their full cellular function is inadequately understood. To examine these enzymes, we developed a robust and automatable cell-based assay based on fluorophore- and fluorescence-quencher-coupled oligonucleotides for the quantitative determination of acidic 5′ exonuclease activity. We validated the assay under knockout and PLD-overexpression conditions and then applied it to characterize PLD3 and PLD4 biochemically. Our experiments revealed PLD3 as the principal acid 5′ exonuclease in HeLa cells, where it showed a markedly higher specific activity compared with PLD4. We further used our newly developed assay to determine the substrate specificity and inhibitory profile of PLD3 and found that proteolytic processing of PLD3 is dispensable for its hydrolytic activity. We followed the expression, proteolytic processing, and intracellular distribution of genetic PLD3 variants previously associated with Alzheimer’s disease and investigated each variant's effect on the 5′ nuclease activity of PLD3, finding that some variants lead to reduced activity, but others not. The development of a PLD3/4-specific biochemical assay will be instrumental in understanding better both nucleases and their incompletely understood roles in vitro and in vivo .

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Quantification and characterization of the 5′ exonuclease activity of the lysosomal nuclease PLD3 by a novel cell-based assay

Cappel¹,

Gonzalez²,

Damme

2021

Journal of Biological Chemistry

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“…Phospholipase D1 and D2 (PLD1 and PLD2), are confirmed to be enzymatically active mammalian PLD isoforms and are druggable proteins [ 2 , 5 ]. PLD3 was identified as a PLD based upon homology as it contains two HKD motifs, but two prior studies informally reported that PLD3 lacks PLD activity, although the data and methodology were not presented [ 6 , 7 ]. The PLD3 gene variants associated with increased late onset AD risk were initially linked to β-amyloid precursor protein (APP) processing [ 1 ] but this could only be replicated in overexpression conditions [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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“…Phospholipase D1 and D2 (PLD1 and PLD2), are confirmed to be enzymatically active mammalian PLD isoforms and are druggable proteins 2,5 . PLD3 was identified as a PLD based upon homology as it contains two HKD motifs, but has been informally reported to lack PLD activity 6 . The PLD3 gene variants associated with increased late onset AD risk were initially linked to β-amyloid precursor protein (APP) processing 1 but this could only be replicated in overexpression conditions 7 .…”

Section: Introductionmentioning

confidence: 99%

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

Nackenoff

Hohman

Neuner

et al. 2019

Preprint

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PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer's disease ABSTRACT 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 determine whether PLD3 is relevant to memory and cognition in sporadic AD, to observe its distribution in normal human brain and AD-affected brain, to describe its subcellular localization, and to evaluate its molecular function. 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 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. In summary, this study identified a new functional mammalian phospholipase D isoform which is lysosomal and closely associated with both βamyloid pathology and cognition.

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PLD3 and spinocerebellar ataxia

Cited by 13 publications

References 4 publications

Quantification and characterization of the 5′ exonuclease activity of the lysosomal nuclease PLD3 by a novel cell-based assay

Quantification and characterization of the 5′ exonuclease activity of the lysosomal nuclease PLD3 by a novel cell-based assay

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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