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Aluminum Inhibits Calpain‐Mediated Proteolysis and Induces Human Neurofilament Proteins to Form ProteaseResistant High Molecular Weight Complexes
Author(s) -
Nixon Ralph A.,
Clarke Jane F.,
Logvinenko Kimberly B.,
Tan Michelle K. H.,
Hoult Mary,
Grynspan Frida
Publication year - 1990
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1990.tb05781.x
Subject(s) - proteolysis , calpain , neurofilament , cytoskeleton , biochemistry , chemistry , glial fibrillary acidic protein , intermediate filament , in vitro , tubulin , biophysics , microbiology and biotechnology , biology , enzyme , microtubule , immunology , immunohistochemistry , cell
We studied the effects of aluminum salts on the degradation of human neurofilament subunits (NF‐H, NF‐M, and NF‐L, the high, middle, and low molecular weight subunits. respectively) and other cytoskeletal proteins using calcium‐activated neutral proteinase (calpain) purified from human brain. Calpain‐mediated proteolysis of NF‐L, tubulin, and glial fibrillary acidic protein (GFAP), three substrates that displayed constant digestion rates in vitro, was inhibited by AlCl 3 (IC 50 = 200 μ M ) and by aluminum lactate (IC 50 = 400 μ M ). Aluminum salts inhibited proteolysis principally by affecting the substrates directly. After exposure to 400 μ M aluminum lactate and removal of unbound aluminum, human cytoskeletal proteins were degraded two‐ to threefold more slowly by calpain. When cytoskeleton preparations were exposed to aluminum salt concentrations of 100 μ M or higher, proportions of NF‐M and NF‐H formed urea‐insoluble complexes of high apparent molecular mass, which were also resistant to proteolysis by calpain. Complexes of tubulin and of GFAP were not observed under the same conditions. Aluminum salts irreversibly inactivated calpain but only at high aluminum concentrations (IC 50 = 1.2 and 2.1 μ M for aluminum lactate and A1C1 3 , respectively), although longer exposure to the ion reduced by twofold the levels required for protease inhibition. These interactions of aluminum with neurofilament proteins and the effects on proteolysis suggest possible mechanisms for the impaired axoplasmic transport of neurofilaments and their accumulation in neuronal perikarya after aluminum administration in vivo.