Neurotrophic effects of progranulin in vivo in reversing motor neuron defects caused by over or under expression of TDP-43 or FUS.
Neurotrophic effects of progranulin in vivo in reversing motor neuron defects caused by over or under expression of TDP-43 or FUS.
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DOI：
10.1371/journal.pone.0174784
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Bennett HP
中科院分区：
文献类型：
--
作者：
Chitramuthu BP;Kay DG;Bateman A;Bennett HP
颗粒蛋白前体（PGRN）是一种在正常和疾病状态下具有多种作用的糖蛋白。GRN基因内的突变导致额颞叶变性（FTLD）。受影响的神经元显示出独特的TAR DNA结合蛋白43（TDP-43）包涵体。PGRN的部分缺失如何导致TDP-43神经病理学尚不清楚。TDP-43包涵体也在患有其他神经退行性疾病（包括肌萎缩性侧索硬化症（ALS）和阿尔茨海默病）的患者的受影响神经元中发现。在ALS中，TDP-43包涵体通常也对融合肉瘤（FUS）具有免疫反应性。TDP-43或FUS内的突变本身在ALS和某些FTLD病例中是神经致病性的。我们利用斑马鱼胚胎尾部初级运动神经元（MN）的生长来研究PGRN与TDP-43和FUS在体内的相互作用。如前所述，斑马鱼PGRN-A（zfPGRN-A）的耗竭与截短的初级MN和受损的运动功能相关。在这里，我们发现zfPGRN-A的耗尽导致初级MN的生长停滞在水平肌间隔处，水平肌间隔是将肌节分成背侧和腹侧隔室的分界线，这是初级运动的最终目的地。成功的轴突生长超出水平肌间隔部分取决于乙酰胆碱受体簇的形成，并且发现这在zfPGRN-A耗尽后紊乱。PGRN逆转zfPGRN-A敲低的影响，但相关基因zfPGRN-1没有影响。TDP-43或FUS的敲低以及人TDP-43和FUS突变体的表达均导致MN异常，其通过hPGRN mRNA的共表达而逆转。TDP-43和FUS都不能逆转由PGRN耗竭引起的MN表型。因此，TDP-43和FUS在基因互补途径中位于PGRN的上游。PGRN克服TDP-43和FUS神经毒性的能力（由于相应基因的部分功能丧失或突变）可能具有治疗相关性。
Progranulin (PGRN) is a glycoprotein with multiple roles in normal and disease states. Mutations within the GRN gene cause frontotemporal lobar degeneration (FTLD). The affected neurons display distinctive TAR DNA binding protein 43 (TDP-43) inclusions. How partial loss of PGRN causes TDP-43 neuropathology is poorly understood. TDP-43 inclusions are also found in affected neurons of patients with other neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In ALS, TDP-43 inclusions are typically also immunoreactive for fused in sarcoma (FUS). Mutations within TDP-43 or FUS are themselves neuropathogenic in ALS and some cases of FTLD. We used the outgrowth of caudal primary motor neurons (MNs) in zebrafish embryos to investigate the interaction of PGRN with TDP-43 and FUS in vivo. As reported previously, depletion of zebrafish PGRN-A (zfPGRN-A) is associated with truncated primary MNs and impaired motor function. Here we found that depletion of zfPGRN-A results in primary MNs outgrowth stalling at the horizontal myoseptum, a line of demarcation separating the myotome into dorsal and ventral compartments that is where the final destination of primary motor is assigned. Successful axonal outgrowth beyond the horizontal myoseptum depends in part upon formation of acetylcholine receptor clusters and this was found to be disorganized upon depletion of zfPGRN-A. PGRN reversed the effects of zfPGRN-A knockdown, but a related gene, zfPGRN-1, was without effect. Both knockdown of TDP-43 or FUS, as well as expression of humanTDP-43 and FUS mutants results in MN abnormalities that are reversed by co-expression of hPGRN mRNA. Neither TDP-43 nor FUS reversed MN phenotypes caused by the depletion of PGRN. Thus TDP-43 and FUS lie upstream of PGRN in a gene complementation pathway. The ability of PGRN to override TDP-43 and FUS neurotoxicity due to partial loss of function or mutation in the corresponding genes may have therapeutic relevance.