Lead Dysregulates Serine/Threonine Protein Phosphatases in Human Neurons |
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Authors: | Abdur Rahman Bruce J Brew Gilles J Guillemin |
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Institution: | (1) Department of Family Sciences, College for Women, Kuwait University, Safat, 13060, Kuwait;(2) Department of Neurology, St Vincent’s Hospital, Darlinghurst, NSW, 2010, Australia;(3) Centre for Applied Medical Research, Department of Neuroimmunology, St Vincent’s Hospital, Darlinghurst, NSW, 2010, Australia;(4) Department of Pharmacology, University of New South Wales, Sydney, NSW, Australia; |
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Abstract: | It is well established that lead (Pb) exposure in humans leads to learning and memory impairment. However, the biological
and molecular mechanisms are still not clearly understood. When over activated, serine/threonine protein phosphatases are
known to function as a constraint on learning and memory. Activation of these phosphatases can also result in cytoskeletal
changes that will adversely affect learning and memory. We investigated the effects of Pb exposure on these phosphatases in
primary cultures of human neurons. Neurons were exposed to physiologically relevant concentrations of Pb (5, 10, 20 and 40 μg/dL)
and total phosphatase and PP2A activities were determined in neuronal lysate using para-nitrophenyl phosphate (pNPP), and
a PP2A-specific phosphopeptide as substrates. Expression of various serine/threonine phosphatases, tau and its phosphorylation
state were determined by Western blot (WB) and immunocytochemistry (ICC). We found that the total phosphatase activity in
the neuronal lysate was increased by 30–50% by all the concentrations of Pb tested. PP2A activity was increased by 5 μg/dL
Pb only. PP1 expression was increased (ranging from 25–50%) by 10, 20 and 40 μg/dL of Pb. PP2B expression was increased substantially
(up to 2.5-fold) by 10 μg/dL Pb, whereas, higher concentrations did not show any effect. On the other hand, Pb (at all concentrations
used) decreased expression of PP2A and PP5. Pb exposure induced substantial hyperphosphorylation of tau at serine 199/202
by 5 and 10 μg/dL Pb, and Threonine 231 at higher doses. Expression of total tau was mostly unaffected by lead. Immunocytochemistry
data confirmed the WB results of expression of PP1, PP2A, tau protein and the phosphorylation of tau. These results support
our hypothesis that Pb exposure up regulates some of the serine/threonine phosphatases (PP1 and PP2B) that are known to impair
memory formation, and suggest a novel mechanism of Pb neurotoxicity. |
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