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Secreted retrovirus-like GAG domain containing protein PEG10 is regulated by UBE3A and is involved in Angelman syndrome pathophysiology

ABSTRACT: Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by mutations that effect expression of the maternal UBE3A allele, which encodes the ubiquitin protein ligase E3A (UBE3A). Although several potential UBE3A targets have been identified, our understanding of relevant disease targets is very limited, and validation in patient-derived cells is lacking. We established human iPSC (hiPSC) control and AS patient-derived neuronal models and demonstrate specific and reciprocal modulation of UBE3A using anti-sense oligonucleotides (ASOs). Through unbiased proteomic analysis we identified proteins whose abundance were directly affected by manipulating UBE3A levels, including the novel human specific PEG10 protein, a secreted retrotransposon derived GAG domain-containing protein. PEG10 protein, but not RNA, was elevated in AS hiPSC-derived neurons as well as in postmortem AS brain tissue, and we showed that its upregulation in patient-derived cells is dependent on both UBE3A and normal proteasome function. Functional analysis revealed that PEG10 binds both RNA and ataxia associated proteins, ATXN2 and ATXN10. PEG10 localizes to stress granules and is secreted in extracellular vesicles, where it regulates vesicle content. AS patient-derived neurons in which either UBE3A was reinstated or PEG10 was reduced, showed a striking similarity in transcriptome changes. In addition, overexpression of PEG10 during mouse brain development affected the migration of the PEG10-overexpressing neurons, suggesting that PEG10 overexpression can affect neuronal function at a critical time during brain development. Taken together these findings imply that PEG10 is a novel secreted UBE3A target, and is involved in AS pathophysiology.

INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Fusion

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Nikhil J. Pandya

PROVIDER: MSV000087654 | MassIVE | Fri Jun 18 05:25:00 BST 2021

REPOSITORIES: MassIVE

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Project description:Cell-based models of many neurological and psychiatric diseases, established by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), have now been reported. While numerous reports have demonstrated that neuronal cells differentiated from hiPSCs are electrophysiologically active mature neurons, the âageâ of these cells relative to cells in the human brain remains unresolved. Comparisons of gene expression profiles of hiPSC-derived neural progenitor cells (NPCs) and neurons to the Allen BrainSpan Atlas indicate that hiPSC neural cells most resemble first trimester neural tissue. Consequently, we posit that hiPSC-derived neural cells may most accurately be used to model the early developmental defects that contribute to disease predisposition rather than the late features of the disease. Though the characteristic symptoms of schizophrenia SZ generally appear late in adolescence, it is now thought to be a neurodevelopmental condition, often predated by a prodromal period that can appear in early childhood. Postmortem studies of SZ brain tissue typically describe defects in mature neurons, such as reduced neuronal size and spine density in the prefrontal cortex and hippocampus, but abnormalities of neuronal organization, particularly in the cortex, have also been reported. We postulated that defects in cortical organization in SZ might result from abnormal migration of neural cells. To test this hypothesis, we directly reprogrammed fibroblasts from SZ patients into hiPSCs and subsequently differentiated these disorder-specific hiPSCs into NPCs. SZ hiPSC differentiated into forebrain NPCs have altered expression of a number of cellular adhesion genes and WNT signaling. Methods: We compared global transcription of forebrain NPCs from six control and four SZ patients by RNAseq. Results: Multi-dimensional scaling (MDS) resolved most SZ and control hiPSC NPC samples; 848 genes were significantly differentially expressed (FDR<0.01) Conclusions: The WNT signaling pathway was enriched 2-fold (fisher exact test p-value = 0.031). 1-2 independent differentiations (biological replicates) for each of four control and four schizophrenia patients were analyzed; samples were generated in parallel to neuron RNAseq data.

Project description:Cell-based models of many neurological and psychiatric diseases, established by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), have now been reported. While numerous reports have demonstrated that neuronal cells differentiated from hiPSCs are electrophysiologically active mature neurons, the “age” of these cells relative to cells in the human brain remains unresolved. Comparisons of gene expression profiles of hiPSC-derived neural progenitor cells (NPCs) and neurons to the Allen BrainSpan Atlas indicate that hiPSC neural cells most resemble first trimester neural tissue. Consequently, we posit that hiPSC-derived neural cells may most accurately be used to model the early developmental defects that contribute to disease predisposition rather than the late features of the disease. Though the characteristic symptoms of schizophrenia SZ generally appear late in adolescence, it is now thought to be a neurodevelopmental condition, often predated by a prodromal period that can appear in early childhood. Postmortem studies of SZ brain tissue typically describe defects in mature neurons, such as reduced neuronal size and spine density in the prefrontal cortex and hippocampus, but abnormalities of neuronal organization, particularly in the cortex, have also been reported. We postulated that defects in cortical organization in SZ might result from abnormal migration of neural cells. To test this hypothesis, we directly reprogrammed fibroblasts from SZ patients into hiPSCs and subsequently differentiated these disorder-specific hiPSCs into NPCs. SZ hiPSC differentiated into forebrain NPCs have altered expression of a number of cellular adhesion genes and WNT signaling. Methods: We compared global transcription of forebrain NPCs from six control and four SZ patients by RNAseq. Results: Multi-dimensional scaling (MDS) resolved most SZ and control hiPSC NPC samples; 848 genes were significantly differentially expressed (FDR<0.01) Conclusions: The WNT signaling pathway was enriched 2-fold (fisher exact test p-value = 0.031).

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Secreted retrovirus-like GAG domain containing protein PEG10 is regulated by UBE3A and is involved in Angelman syndrome pathophysiology

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