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.
Kushkuley
Jacob
J
Center for Cellular Neurobiology and Neurodegeneration Research, Departments of Biological Sciences and Biochemistry, University of Massachusetts Lowell, Lowell, MA 01854, USA.
Metkar
Shailesh
S
Chan
Walter K-H
WK
Lee
Sangmook
S
Shea
Thomas B
TB
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