Dynein cleavage and microtubule accumulation in okadaic acid-treated neurons.
Impairment of protein phosphatase 2A (PP2A) activity is implicated in tau hyperphosphorylation and microtubule (MT) instability in Alzheimer's disease (AD). Here, we report that okadaic acid, an effective PP2A inhibitor, suppresses the levels of acetylated and detyrosinated tubulins, but enhances tyrosinated tubulins in rat primary cortical neuron cultures. Immunocytochemistry experiments reveal that MTs accumulate intensely around soma and proximal neurites, implying impairment of MT transport to distal neurites which is mediated by dynein and dynactin. Here, we reveal that they can be cleaved by calpain. Notably, shortening of process length in OA-treated neurons is alleviated when calpain cleavage activity is inhibited. Based on these results, we propose that calpain-mediated dynein cleavage in OA-treated neurons is responsible for the MT transport deficit, and consequently, neurite retraction.
Yoon
Seung Yong
SY
Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Choi
Jung Eun
JE
Choi
Jin Myung
JM
Kim
Dong Hou
DH
D000107:Acetylation / Q000187:drug effects; D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002122:Calcium Chloride; D002126:Calcium Hydroxide / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004338:Drug Combinations; D004398:Dyneins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008870:Microtubules / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011189:Potassium Chloride; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology; D051381:Rats; D017693:Sodium Bicarbonate; D012965:Sodium Chloride; D014404:Tubulin / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D014404:Tubulin; C036086:calcium hydroxide, calcium chloride, potassium chloride, sodium bicarbonate, sodium chloride drug combination; D019319:Okadaic Acid; D014443:Tyrosine; D012965:Sodium Chloride; D011189:Potassium Chloride; D017693:Sodium Bicarbonate; D054648:Protein Phosphatase 2; D004398:Dyneins; D002122:Calcium Chloride; D002126:Calcium Hydroxide