Endoplasmic reticulum chaperone genes encode effectors of long-term memory

Chatterjee, Snehajyoti; Bahl, Ethan; Mukherjee, Utsav; Walsh, Emily Nicole; Shetty, Mahabalesh; Yan, Amy L.; Vanrobaeys, Yann; Lederman, Joseph D.; Giese, K. Peter; Michaelson, Jacob J.; Abel, Ted

doi:10.1126/sciadv.abm6063

Cited by 24 publications

(25 citation statements)

References 71 publications

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“…Next, we asked whether our model could identify spatial signatures of learning in brain slices of mice following spatial object recognition (SOR) training, a widely used behavioral paradigm to investigate memory mechanisms 24 . Using spatial transcriptomic data from brain slices of SOR-trained and homecage control (HC) mice, we applied our model to predict activity for each spot and clustered all spots into anatomical regions.…”

Section: Resultsmentioning

confidence: 99%

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NEUROeSTIMator: Using Deep Learning to Quantify Neuronal Activation from Single-Cell and Spatial Transcriptomic Data

Bahl

Chatterjee

Elsadany

et al. 2022

Preprint

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Neuronal activity-dependent transcription directs molecular processes that regulate synaptic plasticity, brain circuit development, behavioral adaptation, and long-term memory. Single cell RNA-sequencing technologies (scRNAseq) are rapidly developing and allow for the interrogation of activity-dependent transcription at cellular resolution. Here, we present NEUROeSTIMator, a deep learning model that integrates signals of activation distributed throughout the broader transcriptome to estimate neuronal activation in a way that is robust against differences in species, cell type, and brain region. We demonstrate this method's ability to accurately detect neuronal activity in previously published single cell and time course studies of activity-induced gene expression. Further, using spatial transcriptomic techniques, we demonstrate the model's ability to identify patterns of learning-induced activation. In conclusion, NEUROeSTIMator is a powerful and broadly applicable tool for measuring neuronal activation, whether as a critical covariate or a primary readout of interest.

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Section: Resultsmentioning

confidence: 99%

“…The dataset contains spatial RNA-sequencing of whole brain slices from 1 hour after SOR training or home cage controls. SOR training was performed as previously described 24 . Mouse brain section per mouse was cut at 10 µm thickness and mounted onto each Visium slide capture area.…”

Section: Methodsmentioning

confidence: 99%

NEUROeSTIMator: Using Deep Learning to Quantify Neuronal Activation from Single-Cell and Spatial Transcriptomic Data

Bahl

Chatterjee

Elsadany

et al. 2022

Preprint

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“…In the context of neurodegenerative diseases, a DnaJ domain-containing protein Droj2 has been suggested to be a negative regulator of memory in the Drosophila model of Alzheimer's disease (Ring et al, 2022). ER chaperones Hspa5 and small heat shock protein 22 (sHsp22) were found to improve the impairment in spatial learning and memory deficit in a mice Tauopathy model (Chatterjee et al, 2022;Rodriguez Ospina et al, 2022). Through our work we implicate the chaperone Mrj, to play a crucial role in the regulation of long-term memory in a non-stressed and non-disease condition.…”

Section: Discussionmentioning

confidence: 99%

Mrj an Hsp40 family chaperone regulates the oligomerization of Orb2 and long-term memory

Desai

Singh

Deo

et al. 2022

Preprint

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Orb2 the Drosophila homolog of Cytoplasmic polyadenylation element binding protein (CPEB) forms prion-like oligomers. These oligomers consist of Orb2A and Orb2B isoforms and their formation are dependent on the oligomerization of the Orb2A isoform. Drosophila with a mutation diminishing Orb2A's prion-like oligomerization forms long-term memory but fails to maintain it over time. Since, this prion-like oligomerization of Orb2A plays a crucial role in the maintenance of memory, here we aim to find what regulates this oligomerization. In an immunoprecipitation-based screen, we identify interactors of Orb2A in the Hsp40 and Hsp70 families of proteins. Amongst these, we find an Hsp40 family protein Mrj as a regulator of the conversion of Orb2A to its prion-like form. Mrj interacts with Hsp70 proteins and acts as a chaperone by interfering with the aggregation of pathogenic Huntingtin. Unlike its mammalian homolog, we find Drosophila Mrj is neither an essential gene nor causes any gross neurodevelopmental defect. We observe a loss of Mrj results in a reduction in Orb2 oligomers. Further, the knockdown of Mrj in the mushroom body neurons results in a deficit in long-term memory. Our work implicates a chaperone Mrj in mechanisms of memory regulation through controlling the oligomerization of Orb2A and its association with the translating polysomes.

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“…Candidate transcription factors (TFs) within the PWS-ER chaperone GRN are those with binding site motifs enriched in the promoters of DEGs in PWS β-cells, including, but not limited to the known ATF6 co-factor NFYA, which has roles in insulin secretion and glucose homeostasis [90], as well as PPARB/D also with known roles in β-cell mass and insulin secretion [91]. Intriguingly, a recently published study found that TFs of the nuclear receptor 4A (NR4A) family that participate in long-term memory in mice act through coordinate regulation of numerous ER chaperones [92], with a high degree of concordance with the dysregulated ER chaperones that we identified in PWS INS-1 cell lines; nevertheless, NR4A pathway factors are not DEGs in PWS β-cells.…”

Section: Discussionmentioning

confidence: 99%

Insulin secretion deficits in a Prader-Willi syndrome β-cell model are associated with a concerted downregulation of multiple endoplasmic reticulum chaperones

Koppes

Johnson

Moresco

et al. 2021

Preprint

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Prader-Willi syndrome (PWS) is a multisystem disorder caused by loss of expression of a cluster of paternally-expressed, imprinted genes. Neonatal failure to thrive is followed by childhood-onset hyperphagia, obesity, neurobehavioral abnormalities, and hormonal deficits. Prior evidence from a mouse model with a deletion of the orthologous PWS-gene domain identified abnormal pancreatic islet development with deficient insulin secretion, hypoglucagonemia, and postnatal onset of progressive, lethal hypoglycemia. To investigate the role of PWS-genes in β-cell secretory function, we used CRISPR/Cas9 genome-editing to generate isogenic, clonal INS-1 insulinoma lines with 3.16 Mb deletions of the silent, maternal (control) or active, paternal (PWS) alleles. PWS β-cells showed a significant reduction in basal and glucose-stimulated insulin secretion, signifying a deficiency in cell-autonomous insulin secretion. Parallel proteome and transcriptome studies revealed reduced levels of secreted peptides and twelve endoplasmic reticulum (ER) chaperones, including HSPA5 and HSP90B1. In contrast to the dosage compensation previously seen for ER chaperones in Hspa5 or Hsp90b1 gene knockouts, compensation is precluded by the widespread deficiency of ER chaperones in PWS β-cells. Consistent with the reduced ER chaperone levels, PWS INS-1 β-cells are more sensitive to ER stress, leading to earlier activation of all three arms of the unfolded protein response. These results suggest that a chronic deficit of ER chaperones in PWS β-cells leads to a delay in ER transit and/or folding of insulin and other cargo along the secretory pathway. The findings illuminate the pathophysiological basis of hormone deficits in PWS and implicate PWS-imprinted genes in β-cell secretory pathway function.

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Endoplasmic reticulum chaperone genes encode effectors of long-term memory

Cited by 24 publications

References 71 publications

NEUROeSTIMator: Using Deep Learning to Quantify Neuronal Activation from Single-Cell and Spatial Transcriptomic Data

NEUROeSTIMator: Using Deep Learning to Quantify Neuronal Activation from Single-Cell and Spatial Transcriptomic Data

Mrj an Hsp40 family chaperone regulates the oligomerization of Orb2 and long-term memory

Insulin secretion deficits in a Prader-Willi syndrome β-cell model are associated with a concerted downregulation of multiple endoplasmic reticulum chaperones

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