EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Correlative light and electron microscopy suggests that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington's disease.
ジャーナル・号・ページ	Acta Neuropathol Commun, Vol. 9, Issue 1, Page 70, Year 2021
掲載日	2021年4月14日
著者	Ya Zhou / Thomas R Peskett / Christian Landles / John B Warner / Kirupa Sathasivam / Edward J Smith / Shu Chen / Ronald Wetzel / Hilal A Lashuel / Gillian P Bates / Helen R Saibil /
PubMed 要旨	Huntington's disease (HD) is a late onset, inherited neurodegenerative disorder for which early pathogenic events remain poorly understood. Here we show that mutant exon 1 HTT proteins are recruited ...Huntington's disease (HD) is a late onset, inherited neurodegenerative disorder for which early pathogenic events remain poorly understood. Here we show that mutant exon 1 HTT proteins are recruited to a subset of cytoplasmic aggregates in the cell bodies of neurons in brain sections from presymptomatic HD, but not wild-type, mice. This occurred in a disease stage and polyglutamine-length dependent manner. We successfully adapted a high-resolution correlative light and electron microscopy methodology, originally developed for mammalian and yeast cells, to allow us to correlate light microscopy and electron microscopy images on the same brain section within an accuracy of 100 nm. Using this approach, we identified these recruitment sites as single membrane bound, vesicle-rich endolysosomal organelles, specifically as (1) multivesicular bodies (MVBs), or amphisomes and (2) autolysosomes or residual bodies. The organelles were often found in close-proximity to phagophore-like structures. Immunogold labeling localized mutant HTT to non-fibrillar, electron lucent structures within the lumen of these organelles. In presymptomatic HD, the recruitment organelles were predominantly MVBs/amphisomes, whereas in late-stage HD, there were more autolysosomes or residual bodies. Electron tomograms indicated the fusion of small vesicles with the vacuole within the lumen, suggesting that MVBs develop into residual bodies. We found that markers of MVB-related exocytosis were depleted in presymptomatic mice and throughout the disease course. This suggests that endolysosomal homeostasis has moved away from exocytosis toward lysosome fusion and degradation, in response to the need to clear the chronically aggregating mutant HTT protein, and that this occurs at an early stage in HD pathogenesis.
リンク	Acta Neuropathol Commun / PubMed:33853668 / PubMed Central
手法	EM (トモグラフィー)
構造データ	EMDB-12374: Tomogram of mutant huntingtin inclusion (recruitment foci) in the cytoplasm of hippocampal CA1 neuron in 6 month old zQ175 mice 手法: EM (トモグラフィー) EMDB-12376: Mutant huntingtin containing organelle resembles MVB in 6-month-old zQ175 mice 手法: EM (トモグラフィー) EMDB-12536: Tomogram of mutant huntingtin containing organelle resembles autolysosome in 6-month-old zQ175 mice 手法: EM (トモグラフィー) EMDB-12539: Tomogram of mutant huntingtin containing organelle resembles autolysosome/residual body in 6-month-old zQ175 mice 手法: EM (トモグラフィー)
由来	Mus musculus (ハツカネズミ)