Altered ubiquitination of phospholipase D3 contributes to lysosome dysfunction in Alzheimer’s Disease

Background Proteinopathy is a common feature of multiple neurodegenerative diseases. Recent studies have demonstrated lysosomal dysfunction is closely linked to neurodegenerative proteinopathies. In the context of Alzheimer’s disease (AD), the lysosomal protein phospholipase D3 (PLD3) has been ident...

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Published in:Alzheimer's & dementia 2023-06, Vol.19 (S1), p.n/a
Main Authors: Fernandez, Wilber Romero, Antunes, Lissa Ventura, Katdare, Ketaki A., Balotin, Kylie M., Prusky, Alex, Solopova, Elena, Shostak, Alena, Wang, Emmeline, Lippmann, Ethan S, Schrag, Matthew
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Language:English
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Summary:Background Proteinopathy is a common feature of multiple neurodegenerative diseases. Recent studies have demonstrated lysosomal dysfunction is closely linked to neurodegenerative proteinopathies. In the context of Alzheimer’s disease (AD), the lysosomal protein phospholipase D3 (PLD3) has been identified as a potential molecular player, but PLD3’s distinct role in lysosome function is not completely understood. Method We used immunohistochemistry, western blot, and proximity ligation assays to determine PLD3’s localization, expression level, post‐translational modification and protein‐protein interaction profile. Experiments were performed using iPSC‐neuron cultures and human brain tissue obtained from patients with AD and neurological controls through the Vanderbilt Brain and Biospecimen Bank. Result PLD3 is neuronal widely distributed throughout brain regions relevant to memory and cognition and PLD3 levels were significantly lower in AD brains compared to the controls. We discovered that PLD3 ubiquitination was significantly increased in AD brains relative to the controls, providing a possible explanation for the PLD3 reduction and localization into hallmark pathological structures of the AD brain. Furthermore, PLD3‐ubiquitin complexes were enriched in parenchymal β‐amyloid deposits and intraneuronal tau pathologies, both neuropil threads and neurofibrillary tangles. We provide the first experimental evidence for the physical interaction between PLD3 and Cathepsin D (CTD), both in human brain tissue and iPSC neurons. The interaction between PLD3/CTD was promoted by exposure of iPSC‐neurons to human Aβ seeds isolated from post‐mortem brain, suggesting this protein‐protein interaction is relevant to Aβ pathology. We found this heterodimer was dramatically reduced in AD brain, especially in dystrophic neurites. The loss of this interaction in dystrophic neurites is notable because even though PLD3 levels are reduced in the AD brain, both PLD3 and CTD are present in abundance around β‐amyloid plaques. The loss of PLD3/CTD interaction observed in AD brain is only partly explained by reduced expression of both proteins, so it is likely that an alteration in lysosome function is impacting this protein‐protein interaction. Conclusion This study revealed an important role for both PLD3 ubiquitination and as an interaction partner for CTD within lysosomes. It will be interesting to further dissect the molecular mechanisms underlying the PLD3/CTD interaction.
ISSN:1552-5260
1552-5279
DOI:10.1002/alz.068138