Aluminum induces neurofilament aggregation by stabilizing cross-bridging of phosphorylated c-terminal sidearms

作者：Kushkuley Jacob; Metkar Shailesh; Chan Walter K H; Lee Sangmook; Shea Thomas B^*

来源：Brain Research, 2010, 1322: 118-123.

DOI：10.1016/j.brainres.2010.01.075

• Aluminum
• Neurotoxin
• Neurofilament
• Phosphorylation
• Axonal transport
• Axonal cytoskeleton

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. AlCl(3) induced dose-dependent formation of NF aggregates, ultimately incorporating 100% of detectable NFs. The same concentration of CaCl(2) induced approximately 25% of NFs to form longitudinal dimers and did not induce aggregation. AlCl(3) induced similar percentages of aggregates in the presence or absence of CaCl(2), and CaCl(2) 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.