The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons
The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons
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DOI：
10.1016/j.celrep.2020.02.060
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发表时间：
2020-03-10
期刊：
影响因子：
8.8
通讯作者：
Damme, Markus
中科院分区：
文献类型：
--
作者：
Lueningschror, Patrick;Wemer, Georg;Damme, Markus
编码溶酶体膜蛋白的TMEM106B的遗传变异会影响GRN-(编码原颗粒)和C9orf72-扩展载体中的额颞叶变性(FTLD)，并可能在衰老中发挥作用。为了确定TMEM106B的生理功能，我们建立了TMEM106B缺陷小鼠。这些小鼠出现近端轴突肿胀，原因是LAMP1阳性空泡急剧增大，溶酶体逆行轴突运输增加，脂褐素和自噬小体积聚。巨大的空泡特异性地聚集在远端和轴突起始段内，而不是在周围神经或轴突终末，导致面神经依赖的运动能力受损。这些数据表明TMEM106B参与了LAMP1阳性细胞器在运动神经元中的轴突运输和起始节段的轴突分选。我们的数据为TMEM106B如何影响神经元的溶酶体蛋白分解和降解能力提供了机械性的见解。
Genetic variations in TMEM106B, coding for a lysosomal membrane protein, affect frontotemporal lobar degeneration (FTLD) in GRN- (coding for progranulin) and C9orf72-expansion carriers and might play a role in aging. To determine the physiological function of TMEM106B, we generated TMEM106B-deficient mice. These mice develop proximal axonal swellings caused by drastically enlarged LAMP1-positive vacuoles, increased retrograde axonal transport of lysosomes, and accumulation of lipofuscin and autophagosomes. Giant vacuoles specifically accumulate at the distal end and within the axon initial segment, but not in peripheral nerves or at axon terminals, resulting in an impaired facial-nerve-dependent motor performance. These data implicate TMEM106B in mediating the axonal transport of LAMP1-positive organelles in motoneurons and axonal sorting at the initial segment. Our data provide mechanistic insight into how TMEM106B affects lysosomal proteolysis and degradative capacity in neurons.