Miwa Hideto, Kubo Tomomi, Suzuki Ai, Kondo Tomoyoshi
Department of Neurology, Wakayama Medical University, 811-1 Kimiidera, Wakayama-city, Wakayama 641-8510, Japan.
Neurosci Lett. 2006 Jun 19;401(1-2):146-9. doi: 10.1016/j.neulet.2006.03.003. Epub 2006 Apr 4.
The neuropathological hallmark of idiopathic Parkinson's disease (PD) is dopaminergic neuron degeneration in the substantia nigra. However, it has been suggested that the neurodegenerative process initially may occur in the dorsal motor nucleus of the vagus (DMV). This implies that unidentified environmental toxins or neurotropic pathogens that is capable of passing the mucosal barrier of the gastrointestinal tract might affect the enteric nerve endings of the vagal neurons, possibly resulting in retrograde degeneration of the DMV. The present study aimed to evaluate the effects of proteasome inhibition of the intragastric nerve terminals of the DMV in rats. Following multiple injections of PSI, a selective proteasome inhibitor, or vehicle into the ventral wall of the stomach, the medulla oblongata was studied immunohistologically. In the DMV neurons of rats treated with PSI but not vehicle, alpha-synuclein-immunopositive intracytoplasmic inclusions and activated microglia were observed, predominantly in the left DMV. However, there was no significant loss of neurons. These results suggest that intragastric proteasome inhibition has a retrograde effect on DMV neurons but is insufficient to induce cell death, suggesting no causal linkage between inclusion body formation with proteasome inhibition and neuron death in the DMV. This might also implicate that Lewy body formation in the DMV in PD is possibly related to peroral invasion of environmental toxins that inhibit ubiquitin-proteasome system function.
特发性帕金森病（PD）的神经病理学特征是黑质中的多巴胺能神经元变性。然而，有人提出神经退行性过程最初可能发生在迷走神经背运动核（DMV）。这意味着能够穿过胃肠道黏膜屏障的不明环境毒素或嗜神经病原体可能会影响迷走神经元的肠神经末梢，可能导致DMV的逆行性变性。本研究旨在评估蛋白酶体抑制对大鼠DMV胃内神经末梢的影响。在向胃前壁多次注射选择性蛋白酶体抑制剂PSI或赋形剂后，对延髓进行免疫组织学研究。在接受PSI而非赋形剂治疗的大鼠的DMV神经元中，观察到α-突触核蛋白免疫阳性的胞浆内包涵体和活化的小胶质细胞，主要在左侧DMV。然而，神经元没有明显损失。这些结果表明，胃内蛋白酶体抑制对DMV神经元有逆行作用，但不足以诱导细胞死亡，这表明DMV中包涵体形成与蛋白酶体抑制和神经元死亡之间没有因果联系。这也可能意味着PD中DMV的路易小体形成可能与抑制泛素-蛋白酶体系统功能的环境毒素经口侵入有关。
