Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503.
Neuroscience Graduate Program, College of Natural Science, Michigan State University, East Lansing, Michigan 48824.
J Neurosci. 2021 Mar 3;41(9):2039-2052. doi: 10.1523/JNEUROSCI.1952-20.2020. Epub 2021 Jan 20.
Preclinical studies show a link between subthalamic nucleus (STN) deep brain stimulation (DBS) and neuroprotection of nigrostriatal dopamine (DA) neurons, potentially through brain-derived neurotrophic factor (BDNF) signaling. However, the question of whether DBS of the STN can be disease-modifying in Parkinson's disease (PD) remains unanswered. In particular, the impact of STN DBS on α-synuclein (α-syn) aggregation, inclusion-associated neuroinflammation, and BDNF levels has yet to be examined in the context of synucleinopathy. To address this, we examined the effects of STN DBS on BDNF using the α-syn preformed fibril (PFF) model in male rats. While PFF injection resulted in accumulation of phosphorylated α-syn (pSyn) inclusions in the substantia nigra pars compacta (SNpc) and cortical areas, STN DBS did not impact PFF-induced accumulation of pSyn inclusions in the SNpc. In addition, nigral pSyn inclusions were associated with increased microgliosis and astrogliosis; however, the magnitude of these processes was not altered by STN DBS. Total BDNF protein was not impacted by pSyn inclusions, but the normally positive association of nigrostriatal and corticostriatal BDNF was reversed in rats with PFF-induced nigrostriatal and corticostriatal inclusions. Despite this, rats receiving both STN DBS and PFF injection showed increased BDNF protein in the striatum, which partially restored the normal corticostriatal relationship. Our results suggest that pathologic α-syn inclusions disrupt anterograde BDNF transport within nigrostriatal and corticostriatal circuitry. Further, STN DBS has the potential to exert protective effects by modifying the long-term neurodegenerative consequences of synucleinopathy. An increase in brain-derived neurotrophic factor (BDNF) has been linked to the neuroprotection elicited by subthalamic nucleus (STN) deep brain stimulation (DBS) in neurotoxicant models of Parkinson's disease (PD). However, whether STN DBS can similarly increase BDNF in nigrostriatal and corticostriatal circuitry in the presence of α-synuclein (α-syn) inclusions has not been examined. We examined the impact of STN DBS on rats in which accumulation of α-syn inclusions is induced by injection of α-syn preformed fibrils (PFFs). STN DBS significantly increased striatal BDNF protein in rats seeded with α-syn inclusions and partially restored the normal corticostriatal BDNF relationship. These findings suggest that STN DBS can drive BDNF in the parkinsonian brain and retains the potential for neuroprotection in PD.
临床前研究表明，苍白球内侧部（GPi）深部脑刺激（DBS）与黑质纹状体多巴胺（DA）神经元的神经保护之间存在关联，这可能是通过脑源性神经营养因子（BDNF）信号传递实现的。然而，STN DBS 是否可以在帕金森病（PD）中起到疾病修饰作用仍未得到解答。特别是，在神经核蛋白病的背景下，STN DBS 对α-突触核蛋白（α-syn）聚集、包含相关神经炎症和 BDNF 水平的影响尚未得到检验。为了解决这个问题，我们使用 α-突触核蛋白预形成纤维（PFF）模型在雄性大鼠中检查了 STN DBS 对 BDNF 的影响。虽然 PFF 注射导致黑质致密部（SNpc）和皮质区中磷酸化α-突触核蛋白（pSyn）包含物的积累，但 STN DBS 并没有影响 PFF 诱导的 SNpc 中 pSyn 包含物的积累。此外，黑质 pSyn 包含物与小胶质细胞和星形胶质细胞增生有关；然而，这些过程的程度并没有因 STN DBS 而改变。总的 BDNF 蛋白不受 pSyn 包含物的影响，但在 PFF 诱导的黑质纹状体和皮质纹状体包含物的大鼠中，正常的黑质纹状体和皮质纹状体 BDNF 的正相关关系被逆转。尽管如此，接受 STN DBS 和 PFF 注射的大鼠纹状体中的 BDNF 蛋白增加，部分恢复了正常的皮质纹状体关系。我们的结果表明，病理性α-突触核蛋白在黑质纹状体和皮质纹状体回路中破坏了 BDNF 的顺行运输。此外，STN DBS 有可能通过改变神经核蛋白病的长期神经退行性后果来发挥保护作用。在帕金森病（PD）的神经毒素模型中，已经发现脑源性神经营养因子（BDNF）的增加与苍白球内侧部（STN）深部脑刺激（DBS）引起的神经保护有关。然而，在存在α-突触核蛋白（α-syn）包含物的情况下，STN DBS 是否可以同样增加黑质纹状体和皮质纹状体回路中的 BDNF 尚未得到检验。我们检查了 STN DBS 对注射α-突触核蛋白预形成纤维（PFFs）诱导α-syn 包含物积累的大鼠的影响。STN DBS 显著增加了 PFF 接种大鼠的纹状体 BDNF 蛋白，并部分恢复了正常的皮质纹状体 BDNF 关系。这些发现表明，STN DBS 可以驱动帕金森病大脑中的 BDNF，并保持在 PD 中发挥神经保护的潜力。
