Nakamura, Y;
Shimada, IS;
Maroofian, R;
Falabella, M;
Zaki, MS;
Fujimoto, M;
Sato, E;
Takase, H;
Aoki, S;
Miyauchi, A;
et al.
Nakamura, Y; Shimada, IS; Maroofian, R; Falabella, M; Zaki, MS; Fujimoto, M; Sato, E; Takase, H; Aoki, S; Miyauchi, A; Koshimizu, E; Miyatake, S; Arioka, Y; Honda, M; Higashi, T; Miya, F; Okubo, Y; Ogawa, I; Scardamaglia, A; Miryounesi, M; Alijanpour, S; Ahmadabadi, F; Herkenrath, P; Dafsari, HS; Velmans, C; Al Balwi, M; Vitobello, A; Denommé-Pichon, A-S; Jeanne, M; Civit, A; Abdel-Hamid, MS; Naderi, H; Darvish, H; Bakhtiari, S; Kruer, MC; Carroll, CJ; Ghayoor Karimiani, E; Khailany, RA; Abdulqadir, TA; Ozaslan, M; Bauer, P; Zifarelli, G; Seifi, T; Zamani, M; Al Alam, C; Alvi, JR; Sultan, T; Efthymiou, S; Pope, SAS; Haginoya, K; Matsunaga, T; Osaka, H; Matsumoto, N; Ozaki, N; Ohkawa, Y; Oki, S; Tsunoda, T; Pitceathly, RDS; Taketomi, Y; Houlden, H; Murakami, M; Kato, Y; Saitoh, S
(2024)
Biallelic null variants in PNPLA8 cause microcephaly by reducing the number of basal radial glia.
Brain.
ISSN 1460-2156
https://doi.org/10.1093/brain/awae185
SGUL Authors: Carroll, Christopher John
Abstract
Patatin-like phospholipase domain-containing lipase 8 (PNPLA8), one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. Biallelic variants in PNPLA8 have been associated with a range of paediatric neurodegenerative disorders. However, the phenotypic spectrum, genotype-phenotype correlations and the underlying mechanisms are poorly understood. Here, we newly identified 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide phenotypic spectrum of clinical features. Analysis of the clinical features of current and previously reported individuals (25 affected individuals across 20 families) showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. We found that complete loss of PNPLA8 was associated with the more profound end of the spectrum, with congenital microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Spatial transcriptomics revealed that loss of PNPLA8 altered the fate specification of apical radial glial cells, as reflected by the enrichment of gene sets related to the cell cycle, basal radial glial cells and neural differentiation. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. The reduced number of basal radial glial cells in patient-derived cerebral organoids was rescued, in part, by the addition of lysophosphatidic acid. Our data suggest that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development.
Item Type: |
Article
|
Additional Information: |
© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: |
brain organoid, developmental encephalopathy, iPLA2γ, outer radial glia, brain organoid, developmental encephalopathy, iPLA2γ, outer radial glia, 11 Medical and Health Sciences, 17 Psychology and Cognitive Sciences, Neurology & Neurosurgery |
SGUL Research Institute / Research Centre: |
Academic Structure > REF 2021 user group |
Journal or Publication Title: |
Brain |
ISSN: |
1460-2156 |
Language: |
eng |
Dates: |
Date | Event |
---|
31 July 2024 | Published Online | 20 May 2024 | Accepted |
|
Publisher License: |
Creative Commons: Attribution-Noncommercial 4.0 |
Projects: |
|
PubMed ID: |
39082157 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/116715 |
Publisher's version: |
https://doi.org/10.1093/brain/awae185 |
Statistics
Item downloaded times since 01 Aug 2024.
Actions (login required)
![Edit Item](/style/images/action_view.png) |
Edit Item |