Aluminum induces neurofilament aggregation by stabilizing cross-bridging of phosphorylated c-terminal sidearms.
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.
Center for Cellular Neurobiology and Neurodegeneration Research, Departments of Biological Sciences and Biochemistry, University of Massachusetts Lowell, Lowell, MA 01854, USA.
Jacob
J
Kushkuley
Shailesh
S
Metkar
Walter K-H
WK
Chan
Sangmook
S
Lee
Thomas B
TB
Shea
D000535:Aluminum / Q000633:toxicity*; D000077410:Aluminum Chloride; D017607:Aluminum Compounds / Q000633:toxicity; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects / Q000502:physiology; D002122:Calcium Chloride / Q000633:toxicity; D002712:Chlorides / Q000633:toxicity; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016874:Neurofibrillary Tangles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016900:Neurofilament Proteins / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000502:physiology
D017607:Aluminum Compounds; D002712:Chlorides; D016900:Neurofilament Proteins; D009498:Neurotoxins; D000077410:Aluminum Chloride; D000535:Aluminum; D002122:Calcium Chloride