Regulation of endosomal motility and degradation by amyotrophic lateral sclerosis 2/alsin

被引：43

作者：

Lai, Chen ^{[1
]}

Xie, Chengsong ^{[1
]}

Shim, Hoon ^{[1
]}

Chandran, Jayanth ^{[1
]}

Howell, Brian W. ^{[2
]}

Cai, Huaibin ^{[1
]}

机构：

[1] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[2] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA

来源：

MOLECULAR BRAIN | 2009年 / 2卷

关键词：

Amyotrophic Lateral Sclerosis; Early Endosome; Hereditary Spastic Paraplegia; Motor Neuron Degeneration; ALS2 Gene;

D O I：

10.1186/1756-6606-2-23

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Dysfunction of alsin, particularly its putative Rab5 guanine-nucleotide-exchange factor activity, has been linked to one form of juvenile onset recessive familial amyotrophic lateral sclerosis (ALS2). Multiple lines of alsin knockout (ALS2(-/-)) mice have been generated to model this disease. However, it remains elusive whether the Rab5-dependent endocytosis is altered in ALS2(-/-) neurons. To directly examine the Rab5-mediated endosomal trafficking in ALS2(-/-) neurons, we introduced green fluorescent protein (GFP)-tagged Rab5 into cultured hippocampal neurons to monitor the morphology and motility of Rab5-associated early endosomes. Here we report that Rab5-mediated endocytosis was severely altered in ALS2(-/-) neurons. Excessive accumulation of Rab5-positive vesicles was observed in ALS2(-/-) neurons, which correlated with a significant reduction in endosomal motility and augmentation in endosomal conversion to lysosomes. Consequently, a significant increase in endosome/lysosome-dependent degradation of internalized glutamate receptors was observed in ALS2(-/-) neurons. These phenotypes closely resembled the endosomal trafficking abnormalities induced by a constitutively active form of Rab5 in wild-type neurons. Therefore, our findings reveal a negatively regulatory mechanism of alsin in Rab5-mediated endosomal trafficking, suggesting that enhanced endosomal degradation in ALS2(-/-) neurons may underlie the pathogenesis of motor neuron degeneration in ALS2 and related motor neuron diseases.

引用

页数：12

共 45 条

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