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PMID: 14655753 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Localization of phosphorylated ERK/MAP kinases to mitochondria and autophagosomes in Lewy body diseases.

Brain pathology (Zurich, Switzerland) ·Vol. 13 ·No. 4 ·2003-10-00 ·Pages 473-81

Zhu JH, Guo F, Shelburne J, Watkins S, Chu CT

Abstract

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.

MeSH Terms
Aged Aged, 80 and over Autophagy Cathepsin D/metabolism Cytochrome P-450 Enzyme System/metabolism Endosomes/metabolism,pathology,ultrastructure Female Fluorescent Antibody Technique/methods Humans Lewy Body Disease/enzymology,metabolism,pathology Lysosomes/metabolism,pathology,ultrastructure Male Mesencephalon/metabolism,pathology,ultrastructure Microscopy, Confocal/methods Microscopy, Immunoelectron/methods Mitochondria/metabolism,pathology,ultrastructure Mitogen-Activated Protein Kinases/metabolism Parkinson Disease/enzymology,metabolism,pathology Protein Serine-Threonine Kinases/metabolism Superoxide Dismutase/metabolism rab5 GTP-Binding Proteins/metabolism
Chemicals
Cytochrome P-450 Enzyme System Superoxide Dismutase 60S ribosomal protein kinase MARK1 protein, human Protein Serine-Threonine Kinases Mitogen-Activated Protein Kinases Cathepsin D rab5 GTP-Binding Proteins
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Zhu Jian-Hui
Department of Pathology, Division of Neuropathology, University of Pittsburgh, PA, USA.
Guo Fengli
Shelburne John
Watkins Simon
Chu Charleen T
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Article Info
Journal
Brain pathology (Zurich, Switzerland)
Abbr.
Brain Pathol
ISSN
1015-6305
DOI
10.1111/j.1750-3639.2003.tb00478.x
Published
2003-10-00
Pages
473-81
Language
English
Region
Switzerland
NLM ID
9216781
PMCID
PMC1911206
Subset
IM
Grants
NINDS NIH HHS · R01 NS040817 · United States
NINDS NIH HHS · R01 NS40817 · United States
External Links
PubMed source DOI: 10.1111/j.1750-3639.2003.tb00478.x PMC Full Text View journal details
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