Analysis of hemisphere-dependent effects of unilateral intrastriatal injection of α-synuclein pre-formed fibrils on mitochondrial protein levels, dynamics, and function.
Analysis of hemisphere-dependent effects of unilateral intrastriatal injection of α-synuclein pre-formed fibrils on mitochondrial protein levels, dynamics, and function.
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DOI：
10.1186/s40478-022-01374-z
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发表时间：
2022-05-23
影响因子：
7.1
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中科院分区：
文献类型：
--
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遗传和神经病理学证据强烈表明 α-突触核蛋白的异常形式与神经变性有关。特异性针对丝氨酸 129 (pS129) 磷酸化 α-突触核蛋白 (pS129) 的抗体对帕金森病 (PD) 和其他突触核蛋白病（例如路易体痴呆 (DLB) 和多系统萎缩 (MSA)）特征性的病理性蛋白聚集体具有选择性。尽管大多数突触核蛋白病的病因仍不确定，但大量证据表明线粒体功能障碍。最近开发的基于颅内注射α-突触核蛋白预形成原纤维（PFF）的动物模型为研究α-突触核蛋白聚集体的扩散和神经毒性提供了一个有价值的实验系统，但PFF诱导的蛋白质聚集体对线粒体功能和动力学的影响尚未在体内得到严格的检验。为了帮助填补这一知识空白，我们向小鼠纹状体单侧注射了特征良好的小长度 (< 30 nm) PFF 或单体 α-突触核蛋白对照，并测量了 pS129 α-突触核蛋白免疫反应性聚集体的分布和范围、黑质中酪氨酸羟化酶免疫反应性神经元的损失、 注射后 3 个月和 6 个月时线粒体蛋白质的丰度以及线粒体呼吸链成分的活性。纹状体内注射小长度 PFF，而不是单体 α-突触核蛋白对照，早在注射后 3 个月就在皮质、腹侧中脑和纹状体以及罕见报道的大脑区域（例如海马体）中诱导了强健的 pS129 α-突触核蛋白免疫反应包涵体。注射后 3 个月和 6 个月，在注射 PFF 的半球中观察到黑质酪氨酸羟化酶免疫反应性神经元显着损失。单侧纹状体注射小长度 PFF 还会引起 VDAC1、COX-IV 和 DRP-1 等线粒体蛋白皮质水平的半球依赖性和治疗依赖性变化，以及对侧纹状体中线粒体复合物 I 活性的功能变化。总之，这些数据表明，向小鼠纹状体内注射小长度 PFF 会诱导广泛的双侧蛋白质聚集、显着的单侧黑质细胞损失，并改变对侧线粒体蛋白质和呼吸链活性的水平。我们的数据表明，该动物模型可能有助于研究线粒体功能障碍在 α-突触核蛋白病中的作用，研究 α-突触核蛋白聚集体的半球依赖性效应，以及测试针对线粒体功能障碍和蛋白质聚集的神经保护疗法。
Genetic and neuropathological evidence strongly implicates aberrant forms of α-synuclein in neurodegeneration. Antibodies specific for α-synuclein phosphorylated at serine 129 (pS129) are selective for the pathological protein aggregates that are characteristic of Parkinson’s disease (PD) and other synucleinopathies, such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Although the etiology of most synucleinopathies remains uncertain, a large body of evidence points to mitochondrial dysfunction. The recent development of animal models based on intracranial injection of α-synuclein pre-formed fibrils (PFFs) has provided a valuable experimental system in which to study the spread and neurotoxicity of α-synuclein aggregates, yet the effects of PFF-induced protein aggregates on mitochondrial function and dynamics have not been rigorously examined in vivo. To help fill this knowledge gap, we injected the striatum of mice unilaterally with well-characterized small length (< 30 nm) PFFs or monomeric α-synuclein control and measured the distribution and extent of pS129 α-synuclein-immunoreactive aggregates, the loss of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra, the abundance of mitochondrial proteins, and the activity of mitochondrial respiratory chain components at 3 months and 6 months post injection. Intrastriatal injection of small length PFFs, but not monomeric α-synuclein control, induced robust pS129 α-synuclein immunoreactive inclusions in the cortex, ventral midbrain, and striatum, as well as in rarely reported brain regions, such as the hippocampus, as early as 3 months post injection. Significant loss of nigral tyrosine hydroxylase-immunoreactive neurons was observed in the PFF-injected hemisphere at 3 months and 6 months post injection. The unilateral striatal injection of small length PFFs also caused hemisphere-dependent and treatment-dependent changes in the cortical levels of mitochondrial proteins such as VDAC1, COX-IV, and DRP-1, as well as functional changes in mitochondrial complex I activity in the contralateral striatum. Together, these data demonstrate that intrastriatal injection of mice with small length PFFs induces extensive bilateral protein aggregates, significant unilateral nigral cell loss, and altered contralateral levels of mitochondrial proteins and respiratory chain activity. Our data suggest this animal model may be useful for studying the role of mitochondrial dysfunction in α-synucleinopathies, for studying the hemisphere-dependent effects of α-synuclein aggregates, and for testing neuroprotective therapies that target mitochondrial dysfunction and protein aggregation.
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影响因子：
6.2
作者：
通讯作者：
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影响因子：
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作者：
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影响因子：
3.3
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
168.9
作者：
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通讯作者：
Destée, A