Parkin protects dopaminergic neurons against microtubule-depolymerizing toxins by attenuating microtubule-associated protein kinase activation.
Mitogen-activated protein kinases, originally known as microtubule-associated protein (MAP) kinases, are activated in response to a variety of stimuli. Here we report that microtubule-depolymerizing agents such as colchicine or nocodazole induced strong activation of MAP kinases including JNK, ERK, and p38. This effect was markedly attenuated by parkin, whose mutations are linked to Parkinson disease (PD). Our previous study has shown that parkin stabilizes microtubules through strong interactions mediated by three independent domains. We found that each of the three microtubule-binding domains of parkin was sufficient to reduce MAP kinase activation induced by microtubule depolymerization. The ability to attenuate microtubule depolymerization and the ensuing MAP kinase activation was abrogated in B-lymphocytes and fibroblasts derived from PD patients with parkin mutations such as exon 4 deletion. Such mutations produced truncated parkin proteins lacking any microtubule binding domain and prevented parkin from protecting midbrain dopaminergic neurons against microtubule-depolymerizing toxins such as rotenone or colchicine. Consistent with these, blocking MAP kinase activation in midbrain dopaminergic neurons by knocking down MAP kinase kinases (MKK) significantly reduced the selective toxicity of rotenone or colchicine. Conversely, overexpression of MAP kinases caused marked toxicities that were significantly attenuated by parkin. Thus, the results suggest that parkin protects midbrain dopaminergic neurons against microtubule-depolymerizing PD toxins such as rotenone by stabilizing microtubules to attenuate MAP kinase activation.
Ren
Yong
Y
Department of Physiology and Biophysics, State University of New York, Buffalo, New York 14214, USA.
Jiang
Houbo
H
Yang
Fang
F
Nakaso
Kazuhiro
K
Feng
Jian
J
D000328:Adult; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D003078:Colchicine / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007306:Insecticides / Q000494:pharmacology; D008297:Male; D008636:Mesencephalon / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D015739:Nocodazole / Q000494:pharmacology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary / Q000235:genetics; D012402:Rotenone / Q000494:pharmacology; D050257:Tubulin Modulators / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D007306:Insecticides; D050257:Tubulin Modulators; D012402:Rotenone; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D048049:Extracellular Signal-Regulated MAP Kinases; D015739:Nocodazole; D003078:Colchicine