Lim Angeline, Kraut Rachel
Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, California 95064, USA.
J Neurosci. 2009 Jan 28;29(4):951-63. doi: 10.1523/JNEUROSCI.2582-08.2009.
Impaired axon transport is one of the earliest pathological manifestations of several neurodegenerative diseases, and mutations in motor proteins can exacerbate or cause degeneration (Williamson and Cleveland, 1999; Gunawardena and Goldstein, 2004; Stokin and Goldstein, 2006). Compromised function in lysosomes and other degradative organelles that intersect with the lysosomal pathway are also strongly implicated in neurodegenerative disease pathology (Nixon and Cataldo, 2006; Rubinsztein, 2006). However, any functional link between these two phenomena has not as yet been recognized. Drosophila mutants in blue cheese (bchs) undergo progressive brain degeneration as adults and have shortened life span (Finley et al., 2003), but the cellular function of Bchs and the cause of degeneration have not been identified. A role in lysosomal trafficking is suggested by the homology of Bchs with the vesicle trafficking-associated BEACH (Beige and Chediak-Higashi) domain protein family (Wang et al., 2002; De Lozanne, 2003) and by its genetic interaction with a lysosomal transport pathway (Simonsen et al., 2007). Here, we describe the degeneration of a population of identified larval motor neurons in bchs mutants. We present evidence that Bchs is primarily lysosomal in those motor neurons in wild type and, using live fluorescence imaging of individual motor neurons in intact larvae, show that lysosomal vesicles fail to be transported toward motor neuron termini in bchs mutant and Bchs-overexpressing larvae. We suggest therefore that anterograde transport of lysosomes toward synaptic termini is a key factor in preventing motor neuron degeneration and that Bchs reveals a functional link between the lysosomal degradative pathway and transport.
轴突运输受损是几种神经退行性疾病最早出现的病理表现之一，运动蛋白的突变会加剧或导致神经退行性变（威廉姆森和克利夫兰，1999年；古纳瓦德纳和戈尔茨坦，2004年；斯托金和戈尔茨坦，2006年）。溶酶体和其他与溶酶体途径交叉的降解细胞器功能受损也与神经退行性疾病病理密切相关（尼克松和卡塔尔多，2006年；鲁宾斯坦，2006年）。然而，这两种现象之间的任何功能联系尚未得到确认。蓝纹奶酪（bchs）果蝇突变体成年后会出现进行性脑退化，寿命缩短（芬利等人，2003年），但Bchs的细胞功能和退化原因尚未明确。Bchs与囊泡运输相关的BEACH（米色和切迪亚克-东综合征）结构域蛋白家族具有同源性（王等人，2002年；德洛赞内，2003年），并且与溶酶体运输途径存在遗传相互作用（西蒙森等人，2007年），这表明它在溶酶体运输中发挥作用。在此，我们描述了bchs突变体中一群已鉴定的幼虫运动神经元的退化情况。我们提供证据表明，在野生型的那些运动神经元中，Bchs主要存在于溶酶体中，并且通过对完整幼虫中单个运动神经元进行实时荧光成像，发现溶酶体囊泡在bchs突变体和Bchs过表达的幼虫中无法向运动神经元末端运输。因此，我们认为溶酶体向突触末端的顺行运输是预防运动神经元退化的关键因素，并且Bchs揭示了溶酶体降解途径与运输之间的功能联系。
