Localization of phosphorylated ERK/MAP kinases to mitochondria and autophagosomes in Lewy body diseases.
We previously found that sustained ERK activation contributes to toxicity elicited by the parkinsonian neurotoxin 6-hydroxydopamine. In addition, substantia nigra neurons from patients with incidental Lewy body disease, Parkinson disease (PD), and diffuse Lewy body dementia (DLB) display abnormal phospho-ERK accumulations in the form of discrete cytoplasmic granules. In this study, we investigated the subcellular localization of phospho-ERK immunoreactive granules using double label confocal microscopy and immuno-electron microscopy. A small percentage of phospho-ERK granules co-localized with the early endosome marker Rab5, but not with cathepsin D, 20S proteasome beta-subunit, or cytochrome P450 reductase. Phospho-ERK immunoreactivity was often associated with mitochondrial proteins (MnSOD, 60 kDa and 110 kDa mitochondrial antigens), and some vesicular-appearing phospho-ERK granules appeared to envelop enlarged mitochondria by confocal laser scanning microscopy. Ultrastructural immuno-gold studies revealed phospho-ERK labeling in mitochondria and in association with bundles of approximately 10 nm fibrils. Heavily labeled mitochondria were observed within autophagosomes. As mitochondrial pathology may play a pivotal role in Parkinson and other related neurodegenerative diseases, these studies suggest a potential interaction between dysfunctional mitochondria, autophagy, and ERK signaling pathways.
Zhu
Jian-Hui
JH
Department of Pathology, Division of Neuropathology, University of Pittsburgh, PA, USA.
Guo
Fengli
F
Shelburne
John
J
Watkins
Simon
S
Chu
Charleen T
CT
D000368:Aged; D000369:Aged, 80 and over; D001343:Autophagy; D002402:Cathepsin D / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D005455:Fluorescent Antibody Technique / Q000379:methods; D006801:Humans; D020961:Lewy Body Disease / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008636:Mesencephalon / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018613:Microscopy, Confocal / Q000379:methods; D016253:Microscopy, Immunoelectron / Q000379:methods; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010300:Parkinson Disease / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
D003577:Cytochrome P-450 Enzyme System; D013482:Superoxide Dismutase; C083550:60S ribosomal protein kinase; C105547:MARK1 protein, human; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D002402:Cathepsin D; D020696:rab5 GTP-Binding Proteins