論文 - 詳細
| RRC ID | 78262 |
|---|---|
| 著者 | Takahashi H, Bhagwagar S, Nies SH, Ye H, Han X, Chiasseu MT, Wang G, Mackenzie IR, Strittmatter SM. |
| タイトル | Reduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase. |
| ジャーナル | Nat Commun |
| Abstract |
Comorbid proteinopathies are observed in many neurodegenerative disorders including Alzheimer's disease (AD), increase with age, and influence clinical outcomes, yet the mechanisms remain ill-defined. Here, we show that reduction of progranulin (PGRN), a lysosomal protein associated with TDP-43 proteinopathy, also increases tau inclusions, causes concomitant accumulation of α-synuclein and worsens mortality and disinhibited behaviors in tauopathy mice. The increased inclusions paradoxically protect against spatial memory deficit and hippocampal neurodegeneration. PGRN reduction in male tauopathy attenuates activity of β-glucocerebrosidase (GCase), a protein previously associated with synucleinopathy, while increasing glucosylceramide (GlcCer)-positive tau inclusions. In neuronal culture, GCase inhibition enhances tau aggregation induced by AD-tau. Furthermore, purified GlcCer directly promotes tau aggregation in vitro. Neurofibrillary tangles in human tauopathies are also GlcCer-immunoreactive. Thus, in addition to TDP-43, PGRN regulates tau- and synucleinopathies via GCase and GlcCer. A lysosomal PGRN-GCase pathway may be a common therapeutic target for age-related comorbid proteinopathies. |
| 巻・号 | 15(1) |
| ページ | 1434 |
| 公開日 | 2024-2-16 |
| DOI | 10.1038/s41467-024-45692-3 |
| PII | 10.1038/s41467-024-45692-3 |
| PMID | 38365772 |
| PMC | PMC10873339 |
| MeSH | Alzheimer Disease* / metabolism Animals Glucosylceramidase / genetics Glucosylceramidase / metabolism Humans Male Mice Progranulins Proteostasis Deficiencies* Tauopathies* alpha-Synuclein / genetics alpha-Synuclein / metabolism tau Proteins / genetics tau Proteins / metabolism |
| IF | 12.121 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 14 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 実験動物マウス | RBRC02370 |