Chou S M, Wang H S, Taniguchi A
Forbes Norris ALS/MDA Research Center, California Pacific Medical Center, San Francisco 94115, USA.
J Neurol Sci. 1996 Aug;139 Suppl:16-26. doi: 10.1016/0022-510x(96)00090-1.
A number of free radicals such as superoxide and nitric oxide may cause damage to motor neurons but the exact mechanism remains to be elucidated. A potent free radical, peroxynitrite, is readily formed from superoxide and nitric oxide, which captures superoxide three times faster than SOD-1. Peroxynitrite may nitrate tyrosine residues of light neurofilaments (NF-I), thereby altering NF assembly and causing NF accumulation in motor neurons. To test this hypothesis we have probed the massive NF aggregates which are histopathological hallmarks of ALS/MND with immunohistochemistry. We investigated localization of reaction products related to SOD-1, nitric oxide synthase (NOS) and cyclic GMP activities. Our studies show colocalization of NF aggregates with SOD-1/b-NOS/calmodulin /citrulline/cGMP and nitrotyrosine in upper motor neuron conglomerates (Cgl) and lower motor neutron axonal spheroids (Axs). This strongly supports the notion that peroxynitrite deranges NF phosphorylation and assembly, by nitrating tyrosine residues in NF-L. Impaired phosphorylation of NF subunits, either at NF-I or at NF-H, may affect the slow axonal transport culminating in proximo-distal accumulation of NF and slowly progressive motoneuron death.
超氧化物和一氧化氮等多种自由基可能会对运动神经元造成损伤，但其确切机制仍有待阐明。一种强效自由基——过氧亚硝酸盐，很容易由超氧化物和一氧化氮形成，它捕获超氧化物的速度比超氧化物歧化酶1（SOD-1）快三倍。过氧亚硝酸盐可能会使轻链神经丝（NF-I）的酪氨酸残基硝化，从而改变神经丝的组装，并导致运动神经元中神经丝的积累。为了验证这一假设，我们用免疫组织化学方法检测了作为肌萎缩侧索硬化症/运动神经元病组织病理学特征的大量神经丝聚集体。我们研究了与SOD-1、一氧化氮合酶（NOS）和环磷酸鸟苷活性相关的反应产物的定位。我们的研究表明，在上运动神经元团块（Cgl）和下运动神经元轴突球状体（Axs）中，神经丝聚集体与SOD-1/β-NOS/钙调蛋白/瓜氨酸/环磷酸鸟苷和硝基酪氨酸共定位。这有力地支持了过氧亚硝酸盐通过使神经丝轻链（NF-L）中的酪氨酸残基硝化而扰乱神经丝磷酸化和组装的观点。神经丝亚基在NF-I或NF-H处的磷酸化受损，可能会影响轴突的慢速运输，最终导致神经丝在近端到远端的积累以及运动神经元的缓慢进行性死亡。
