Impaired mitochondrial accumulation and Lewy pathology in neuron-specific FBXO7-deficient mice.
Impaired mitochondrial accumulation and Lewy pathology in neuron-specific FBXO7-deficient mice.
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DOI：
10.1186/s13041-022-00936-5
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发表时间：
2022-06-14
期刊：
影响因子：
3.6
通讯作者：
中科院分区：
文献类型：
--
作者：
帕金森病是第二大最常见的神经退行性疾病，其特征是黑质纹状体多巴胺神经元的丧失。FBXO7 (F-box蛋白仅7)（PARK15）突变导致早发性帕金森病。FBXO7是SCF （SKP1/cullin-1/F-box蛋白）E3泛素连接酶复合物的一个亚基，但其神经元相关性和功能尚未阐明。为了确定其在神经元中的功能，我们通过将先前表征的FBXO7flox小鼠（FBXO7flox/flox）与nesting - cre小鼠（nesting - cre）杂交，产生神经元细胞特异性FBXO7条件敲除小鼠（FBXO7flox/flox: nesting - cre）。Fbxo7flox/flox: nesting - cre小鼠表现出幼年期运动功能障碍，包括后肢缺陷和多巴胺能神经元数量减少。多巴胺能神经元和皮质神经元线粒体碎片化。此外，在神经元中还发现了p62和synuclein阳性的路易体样聚集体。我们的研究结果强调了p62的稳态水平在控制细胞内包涵体形成中的意想不到的作用，p62是由包括泛素-蛋白酶体系统在内的非自噬系统调节的。这些数据表明，与蛋白质水解和线粒体降解系统相关的病理过程在PD的发病机制中起着至关重要的作用。
Parkinson’s disease, the second most common neurodegenerative disorder, is characterized by the loss of nigrostriatal dopamine neurons. FBXO7 (F-box protein only 7) (PARK15) mutations cause early-onset Parkinson’s disease. FBXO7 is a subunit of the SCF (SKP1/cullin-1/F-box protein) E3 ubiquitin ligase complex, but its neuronal relevance and function have not been elucidated. To determine its function in neurons, we generated neuronal cell-specific FBXO7 conditional knockout mice (FBXO7flox/flox: Nestin-Cre) by crossing previously characterized FBXO7 floxed mice (FBXO7flox/flox) with Nestin-Cre mice (Nestin-Cre). The resultant Fbxo7flox/flox: Nestin-Cre mice showed juvenile motor dysfunction, including hindlimb defects and decreased numbers of dopaminergic neurons. Fragmented mitochondria were observed in dopaminergic and cortical neurons. Furthermore, p62- and synuclein-positive Lewy body-like aggregates were identified in neurons. Our findings highlight the unexpected role of the homeostatic level of p62, which is regulated by a non-autophagic system that includes the ubiquitin–proteasome system, in controlling intracellular inclusion body formation. These data indicate that the pathologic processes associated with the proteolytic and mitochondrial degradation systems play a crucial role in the pathogenesis of PD.
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影响因子：
4.6
作者：
Sato S;Uchihara T;Fukuda T;Noda S;Kondo H;Saiki S;Komatsu M;Uchiyama Y;Tanaka K;Hattori N
通讯作者：
Hattori N
DOI：
10.1083/jcb.200910140
发表时间：
2010-04-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Matsuda N;Sato S;Shiba K;Okatsu K;Saisho K;Gautier CA;Sou YS;Saiki S;Kawajiri S;Sato F;Kimura M;Komatsu M;Hattori N;Tanaka K
通讯作者：
Tanaka K
DOI：
10.1083/jcb.200809125
发表时间：
2008-12-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Narendra D;Tanaka A;Suen DF;Youle RJ
通讯作者：
Youle RJ
影响因子：
4.7
作者：
SCHAPIRA, AHV;COOPER, JM;MARSDEN, CD
通讯作者：
MARSDEN, CD
影响因子：
25
作者：
Burchell, Victoria S.;Nelson, David E.;Sanchez-Martinez, Alvaro;Delgado-Camprubi, Marta;Ivatt, Rachael M.;Pogson, Joe H.;Randle, Suzanne J.;Wray, Selina;Lewis, Patrick A.;Houlden, Henry;Abramov, Andrey Y.;Hardy, John;Wood, Nicholas W.;Whitworth, Alexander J.;Laman, Heike;Plun-Favreau, Helene
通讯作者：
Plun-Favreau, Helene