Repetitive mild TBI causes pTau aggregation in nigra without altering preexisting fibril induced Parkinson's-like pathology burden.
Repetitive mild TBI causes pTau aggregation in nigra without altering preexisting fibril induced Parkinson's-like pathology burden.
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DOI：
10.1186/s40478-022-01475-9
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发表时间：
2022-11-26
影响因子：
7.1
通讯作者：
中科院分区：
文献类型：
--
作者：
人口研究表明，创伤性脑损伤（TBI）与帕金森病（PD）的风险增加有关，在有TBI病史的美国退伍军人中，这种风险高出56%。最常见的TBI类型是轻度（mTBI），经常在运动员，军人和家庭暴力受害者中反复发生。PD的典型特征是由黑质中脑部（SNpc）多巴胺能神经元的进行性神经变性引起的精细运动控制缺陷。这种神经变性之前是特征性α突触核蛋白（αSyn）蛋白包涵体的可预测扩散。重复性mTBI（r-mTBI）是否可以核PD病理或加速前驱PD病理仍然是未知的。为了回答这个问题，构建了一种损伤装置，用于向大鼠递送无需手术的r-mTBI，并通过颅内注射重组αSyn预形成的原纤维诱导类人PD病理学。在3个月的终点，r-mTBI引起整个大脑的脑软化，这让人想起有mTBI病史的患者的神经影像学结果，伴有星形胶质细胞扩张和小胶质细胞活化。与PD最密切相关的病理学，包括SNpc中的多巴胺能神经变性和存活神经元中的路易体样αSyn包涵体负荷，不是由r-mTBI从头产生的，也不是原纤维诱导的既存病理学加速。然而，r-mTBI确实引起具有和不具有预先存在的PD样病理的大鼠的黑质中磷酸化Tau（pTau）蛋白的聚集。还发现pTau聚集与PFF诱导的αSyn病理学共定位，而没有r-mTBI。这些结果表明，r-mTBI诱导的多巴胺能神经元中的pTau聚集体沉积可能会产生有利于αSyn病理成核的环境，并可能增加预先存在的蛋白质聚集体负荷。在线版本包含补充材料，可通过10.1186/s40478-022-01475-9获得。
Population studies have shown that traumatic brain injury (TBI) is associated with an increased risk for Parkinson’s disease (PD) and among U.S. Veterans with a history of TBI this risk is 56% higher. The most common type of TBI is mild (mTBI) and often occurs repeatedly among athletes, military personnel, and victims of domestic violence. PD is classically characterized by deficits in fine motor movement control resulting from progressive neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) midbrain region. This neurodegeneration is preceded by the predictable spread of characteristic alpha synuclein (αSyn) protein inclusions. Whether repetitive mTBI (r-mTBI) can nucleate PD pathology or accelerate prodromal PD pathology remains unknown. To answer this question, an injury device was constructed to deliver a surgery-free r-mTBI to rats and human-like PD pathology was induced by intracranial injection of recombinant αSyn preformed fibrils. At the 3-month endpoint, the r-mTBI caused encephalomalacia throughout the brain reminiscent of neuroimaging findings in patients with a history of mTBI, accompanied by astrocyte expansion and microglial activation. The pathology associated most closely with PD, which includes dopaminergic neurodegeneration in the SNpc and Lewy body-like αSyn inclusion burden in the surviving neurons, was not produced de novo by r-mTBI nor was the fibril induced preexisting pathology accelerated. r-mTBI did however cause aggregation of phosphorylated Tau (pTau) protein in nigra of rats with and without preexisting PD-like pathology. pTau aggregation was also found to colocalize with PFF induced αSyn pathology without r-mTBI. These findings suggest that r-mTBI induced pTau aggregate deposition in dopaminergic neurons may create an environment conducive to αSyn pathology nucleation and may add to preexisting proteinaceous aggregate burden. The online version contains supplementary material available at 10.1186/s40478-022-01475-9.
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影响因子：
1.9
作者：
Bigler ED;Abildskov TJ;Goodrich-Hunsaker NJ;Black G;Christensen ZP;Huff T;Wood DM;Hesselink JR;Wilde EA;Max JE
通讯作者：
Max JE
影响因子：
7.1
作者：
Harms AS;Delic V;Thome AD;Bryant N;Liu Z;Chandra S;Jurkuvenaite A;West AB
通讯作者：
West AB
影响因子：
21.3
作者：
Fujiwara, H;Hasegawa, M;Iwatsubo, T
通讯作者：
Iwatsubo, T
影响因子：
11
作者：
Doder, M;Jahanshahi, M;Lees, AJ
通讯作者：
Lees, AJ
DOI：
10.1016/j.mcn.2015.03.001
发表时间：
2015-05
期刊：
Molecular and cellular neurosciences
影响因子：
--
作者：
Gardner RC;Yaffe K
通讯作者：
Yaffe K