Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA.
Department of Genetics, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Genetics. 2023 Mar 2;223(3). doi: 10.1093/genetics/iyad008.
Traumatic brain injury (TBI) outcomes vary greatly among individuals, but most of the variation remains unexplained. Using a Drosophila melanogaster TBI model and 178 genetically diverse lines from the Drosophila Genetic Reference Panel (DGRP), we investigated the role that genetic variation plays in determining TBI outcomes. Following injury at 20-27 days old, DGRP lines varied considerably in mortality within 24 h ("early mortality"). Additionally, the disparity in early mortality resulting from injury at 20-27 vs 0-7 days old differed among DGRP lines. These data support a polygenic basis for differences in TBI outcomes, where some gene variants elicit their effects by acting on aging-related processes. Our genome-wide association study of DGRP lines identified associations between single nucleotide polymorphisms in Lissencephaly-1 (Lis-1) and Patronin and early mortality following injury at 20-27 days old. Lis-1 regulates dynein, a microtubule motor required for retrograde transport of many cargoes, and Patronin protects microtubule minus ends against depolymerization. While Patronin mutants did not affect early mortality, Lis-1 compound heterozygotes (Lis-1x/Lis-1y) had increased early mortality following injury at 20-27 or 0-7 days old compared with Lis-1 heterozygotes (Lis-1x/+), and flies that survived 24 h after injury had increased neurodegeneration but an unaltered lifespan, indicating that Lis-1 affects TBI outcomes independently of effects on aging. These data suggest that Lis-1 activity is required in the brain to ameliorate TBI outcomes through effects on axonal transport, microtubule stability, and other microtubule proteins, such as tau, implicated in chronic traumatic encephalopathy, a TBI-associated neurodegenerative disease in humans.
创伤性脑损伤（TBI）的结果在个体之间差异很大，但大多数差异仍未得到解释。我们使用黑腹果蝇 TBI 模型和来自果蝇遗传参考面板（DGRP）的 178 个具有遗传多样性的品系，研究了遗传变异在确定 TBI 结果中的作用。在 20-27 天大时受伤后，DGRP 品系在 24 小时内的死亡率（“早期死亡率”）有很大差异。此外，在 20-27 天与 0-7 天大受伤时导致的早期死亡率差异在 DGRP 品系之间也有所不同。这些数据支持 TBI 结果存在多基因基础，其中一些基因变异通过作用于与衰老相关的过程来发挥其作用。我们对 DGRP 品系的全基因组关联研究发现，Lissencephaly-1（Lis-1）和 Patronin 中的单核苷酸多态性与 20-27 天大受伤后的早期死亡率之间存在关联。Lis-1 调节动力蛋白，这是一种微管动力蛋白，对于许多货物的逆行运输是必需的，而 Patronin 保护微管的负端免受解聚。虽然 Patronin 突变体不会影响早期死亡率，但与 Lis-1 杂合子（Lis-1x/+）相比，Lis-1 复合杂合子（Lis-1x/Lis-1y）在 20-27 天或 0-7 天大受伤后具有更高的早期死亡率，并且在受伤后存活 24 小时的果蝇具有更高的神经退行性变，但寿命没有改变，表明 Lis-1 通过对轴突运输、微管稳定性和其他微管蛋白（如 tau）的影响，独立于对衰老的影响，影响 TBI 结果。这些数据表明，Lis-1 活性在大脑中是必需的，通过对轴突运输、微管稳定性和其他微管蛋白（如 tau）的影响，改善 TBI 结果，tau 与慢性创伤性脑病有关，这是一种人类 TBI 相关的神经退行性疾病。
