Institute of Clinical Neurobiology, University Hospital Wuerzburg, University of Wuerzburg, 97078 Wuerzburg, Germany.
Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
Cell Rep. 2020 Mar 10;30(10):3506-3519.e6. doi: 10.1016/j.celrep.2020.02.060.
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.
TMEM106B 基因发生变异会影响编码颗粒体蛋白前体（GRN）和 C9orf72 扩展的额颞叶痴呆（FTLD）的携带者，并可能在衰老过程中发挥作用。为了确定 TMEM106B 的生理功能，我们生成了 TMEM106B 缺陷型小鼠。这些小鼠表现出近端轴突肿胀，这是由 LAMP1 阳性空泡明显增大引起的，溶酶体的逆行轴突运输增加，脂褐素和自噬体积累。巨大的空泡特异性地在轴突起始段的远端和内部积累，但不在周围神经或轴突末端积累，导致面神经依赖性运动功能受损。这些数据表明 TMEM106B 介导了运动神经元中 LAMP1 阳性细胞器的轴突运输和初始段的轴突分拣。我们的数据为 TMEM106B 如何影响神经元中的溶酶体蛋白水解和降解能力提供了机制上的见解。
