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| Status |
Public on Jan 18, 2024 |
| Title |
Progranulin–glucocerebrosidase complex regulates tau and alpha-synuclein inclusions to alter phenotypes in tauopathy |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Many neurodegenerative disorders including Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are characterized by abnormal protein deposition and frequently show comorbid pathology. Progranulin (PGRN) is implicated not only in TDP-43 but in tau and alpha-synuclein proteinopathies. However, the underlying mechanisms are unknown. Here, we generated P301S tau transgenic mice with PGRN haploinsufficiency and loss and found that those mice exhibit exacerbated disinhibition phenotype while showing attenuated memory impairment, hippocampal atrophy, and transcriptomic changes. Remarkably, the phenotypic alteration was accompanied by an increase in tau inclusions, which are positive for alpha-synuclein, a PGRN binding partner beta-glucocerebrosidase (GCase), and its substrate glucosylceramide. GCase inhibition or PGRN deficiency enhanced tau aggregation induced by AD-derived tau seeds in neurons. In vitro, GCase and glucosylceramide promoted P301S tau aggregation. Similar co-pathology was observed in AD and FTLD-GRN patients.
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| Overall design |
18 samples (hippocampus) from 6 genotypes with 3 biological replicates were individually processed and sequenced. Nuclei were isolated from hippocampi using Nuclei EZ Prep Kit (SIGMA #NUC-101). Libraries were prepared using Chromium Single Cell 3” Reagent Kits v3 (10X Genomics) . The libraries underwent HiSeq paired-end sequencing with a sequence depth of 200 million reads per sample using NovaSeq instrument (Ilumina).
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| Contributor(s) |
Takahashi H, Bhagwagar S, Nies SH, Chiasseu MT, Wang G, Mackenzie I, Strittmatter SM |
| Citation(s) |
38365772 |
| |
| Submission date |
Jul 22, 2021 |
| Last update date |
Mar 07, 2024 |
| Contact name |
Hideyuki Takahashi |
| Organization name |
Yale University
|
| Department |
Neuroscience
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| Lab |
Strittmatter
|
| Street address |
295 Congress Ave. BCMM431
|
| City |
New Haven |
| State/province |
Connecticut |
| ZIP/Postal code |
06536-0812 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (18)
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| Relations |
| BioProject |
PRJNA749056 |
| SRA |
SRP329514 |
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