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

Brain Pathol. 2003 Oct;13(4):473-81. doi: 10.1111/j.1750-3639.2003.tb00478.x.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Autophagy*
  • Cathepsin D / metabolism
  • Cytochrome P-450 Enzyme System / metabolism
  • Endosomes / metabolism
  • Endosomes / pathology
  • Endosomes / ultrastructure
  • Female
  • Fluorescent Antibody Technique / methods
  • Humans
  • Lewy Body Disease / enzymology*
  • Lewy Body Disease / metabolism
  • Lewy Body Disease / pathology
  • Lysosomes / metabolism
  • Lysosomes / pathology
  • Lysosomes / ultrastructure
  • Male
  • Mesencephalon / metabolism
  • Mesencephalon / pathology
  • Mesencephalon / ultrastructure
  • Microscopy, Confocal / methods
  • Microscopy, Immunoelectron / methods
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mitochondria / ultrastructure
  • Mitogen-Activated Protein Kinases / metabolism*
  • Parkinson Disease / enzymology
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Protein-Serine-Threonine Kinases / metabolism
  • Superoxide Dismutase / metabolism
  • rab5 GTP-Binding Proteins / metabolism

Substances

  • 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