Center for Cellular Neurobiology and Neurodegeneration Research, Departments of Biological Sciences and Biochemistry, University of Massachusetts Lowell, Lowell, MA 01854, USA.
Brain Res. 2010 Mar 31;1322:118-23. doi: 10.1016/j.brainres.2010.01.075. Epub 2010 Feb 2.
Exposure to neurotoxin aluminum neurotoxicity is accompanied by the perikaryal accumulation of tangles of phosphorylated neurofilaments (NFs). We examined their formation and reversibility under cell-free conditions. AlCl3 induced dose-dependent formation of NF aggregates, ultimately incorporating 100% of detectable NFs. The same concentration of CaCl2 induced approximately 25% of NFs to form longitudinal dimers and did not induce aggregation. AlCl3 induced similar percentages of aggregates in the presence or absence of CaCl2, and CaCl2 could not reduce pre-formed aggregates. CaCl(2)-induced dimers and AlCl(3)-induced aggregates were prevented by prior NF dephosphorylation. While CaCl(2)-induced dimers were dissociated by phosphatase treatment, AlCl(3)-induced aggregates were only reduced by approximately 50%, suggesting that aggregates may sequester phosphorylation sites. Since phosphatases regulate NF phosphorylation within perikarya, inhibition of NF dephosphorylation by aluminum would promote perikaryal NF phosphorylation and foster precocious phospho-dependent NF-NF associations. These findings are consistent with the notion that prolonged interactions induced among phospho-NFs by the trivalent aluminum impairs axonal transport and promotes perikaryal aggregation.
神经毒素铝的神经毒性会导致神经元原纤维（NFs）的磷酸化缠结在胞体中积累。我们在无细胞条件下研究了它们的形成和可逆性。AlCl3 诱导 NF 聚集体的剂量依赖性形成，最终包含可检测到的 NFs 的 100%。相同浓度的 CaCl2 诱导大约 25%的 NFs 形成纵向二聚体，并且不会诱导聚集。AlCl3 在有或没有 CaCl2 的情况下诱导相似百分比的聚集体，并且 CaCl2 不能减少预先形成的聚集体。NF 去磷酸化可防止 CaCl2 诱导的二聚体和 AlCl3 诱导的聚集体的形成。虽然 CaCl2 诱导的二聚体可通过磷酸酶处理解离，但 AlCl3 诱导的聚集体仅减少约 50%，表明聚集体可能隔离磷酸化位点。由于磷酸酶在胞体中调节 NF 磷酸化，因此铝对 NF 去磷酸化的抑制会促进胞体 NF 磷酸化，并促进早熟的磷酸依赖的 NF-NF 相互作用。这些发现与以下观点一致：三价铝诱导的磷酸化 NF 之间的长时间相互作用会损害轴突运输并促进胞体聚集。
