Golgipathies reveal the critical role of the sorting machinery in brain and skeletal development

Ghouzzi, Vincent El; Boncompain, Gaëlle

doi:10.1038/s41467-022-35101-y

Cited by 4 publications

(1 citation statement)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this work, we show that Golgi deployment is also conserved in human iPSC-derived neurons, a finding that was recently published while we were preparing this manuscript (Wang, Cho et al 2023). It remains to be determined if this phenomenon also occurs in human brain and if it has role in human neurodevelopment, as there is increased interest in the role of the GC in disease (Rasika, Passemard et al 2018, Boecker, Olenick et al 2020, El Ghouzzi and Boncompain 2022). It is of note that basal activation levels of downstream targets (e.g., pERK, pAKT, pCREB) in untreated cells are mostly unchanged between WT and AP-4-KO neurons and that it is only upon the addition of Reelin that these defects become readily apparent.…”

Section: Discussionmentioning

confidence: 99%

The Reelin Receptor ApoER2 is a Cargo for the Adaptor Protein Complex AP-4: Implications for Hereditary Spastic Paraplegia

Caracci,

Pizarro,

Alarcón-Godoy

et al. 2023

Preprint

View full text Add to dashboard Cite

Adaptor protein complex 4 (AP-4) is a heterotetrameric complex that promotes protein export from thetrans-Golgi network. Mutations in each of the AP-4 subunits cause a complicated form of Hereditary Spastic Paraplegia (HSP). Herein, we report that ApoER2, a receptor in the Reelin signaling pathway, is a cargo of the AP-4 complex. We identify the motif ISSF/Y within the ApoER2 cytosolic domain as necessary for interaction with the canonical signal-binding pocket of the µ4 (AP4M1) subunit of AP-4.AP4E1-knock-out (KO) HeLa cells and hippocampal neurons fromAp4e1-KO mice display increased Golgi localization of ApoER2. Furthermore, hippocampal neurons fromAp4e1-KO mice andAP4M1-KO human iPSC-derived cortical i3Neurons exhibit reduced ApoER2 protein expression. Analyses of biosynthetic transport of ApoER2 reveal differential post-Golgi trafficking of the receptor, with lower axonal distribution in KO compared to wild-type neurons, indicating a role of AP-4 and the ISSF/Y motif in the axonal localization of ApoER2. Finally, analyses of Reelin signaling in mouse hippocampal and human cortical KO neurons show that AP4 deficiency causes no changes in Reelin-dependent activation of the AKT pathway and only mild changes in Reelin-induced dendritic arborization, but reduces Reelin-induced ERK phosphorylation, CREB activation, and Golgi deployment. Altogether, this work establishes ApoER2 as a novel cargo of the AP-4 complex, suggesting that defects in the trafficking of this receptor and in the Reelin signaling pathway could contribute to the pathogenesis of HSP caused by mutations in AP-4 subunits.

show abstract

Section: Discussionmentioning

confidence: 99%

The Reelin Receptor ApoER2 is a Cargo for the Adaptor Protein Complex AP-4: Implications for Hereditary Spastic Paraplegia

Caracci,

Pizarro,

Alarcón-Godoy

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

The Reelin receptor ApoER2 is a cargo for the adaptor protein complex AP-4: Implications for Hereditary Spastic Paraplegia

Caracci,

Pizarro,

Alarcón-Godoy

et al. 2024

Progress in Neurobiology

View full text Add to dashboard Cite

Plasma acellular transcriptome contains Parkinson’s disease signatures that can inform clinical diagnosis

Beric,

Cisterna-García,

Martin

et al. 2024

Preprint

View full text Add to dashboard Cite

We aimed to identify plasma cell-free transcripts (cfRNA) associated with Parkinson disease (PD) that also have a high predictive value to differentiate PD from healthy controls. Leveraging two independent populations from two different movement disorder centers we identified 2,188 differentially expressed cfRNAs after meta-analysis. The identified transcripts were enriched in PD relevant pathways, such as PD (p=9.261x0-4), ubiquitin-mediated proteolysis (p=7.41x10-5) and endocytosis (p=4.21x10-6). Utilizing in-house and publicly available brain, whole blood, and acellular plasma transcriptomic and proteomic PD datasets, we found significant overlap across dysregulated biological species in the different tissues and the different biological layers. We developed three predictive models containing increasing number of transcripts that can distinguish PD from healthy control with an area under the ROC Curve (AUC) >=0.85. Finally, we showed that several of the predictive transcripts significantly correlate with symptom severity measured by UPDRS-III. Overall, we have demonstrated that cfRNA contains pathological signatures and has the potential to be utilized as biomarker to aid in PD diagnostics and monitoring.

show abstract

Golgipathies reveal the critical role of the sorting machinery in brain and skeletal development

Abstract: Check for updates1234567890():,; 1234567890():,;

Cited by 4 publications

References 38 publications

The Reelin Receptor ApoER2 is a Cargo for the Adaptor Protein Complex AP-4: Implications for Hereditary Spastic Paraplegia

The Reelin Receptor ApoER2 is a Cargo for the Adaptor Protein Complex AP-4: Implications for Hereditary Spastic Paraplegia

The Reelin receptor ApoER2 is a cargo for the adaptor protein complex AP-4: Implications for Hereditary Spastic Paraplegia

Plasma acellular transcriptome contains Parkinson’s disease signatures that can inform clinical diagnosis

Contact Info

Product

Resources

About