Extrusion of misfolded and aggregated proteins - a protective strategy of aging neurons?
| Autor: | Doehner, Jana, Genoud, Christel, Imhof, Claudine, Krstic, Dimitrije, Knuesel, Irene |
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| Přispěvatelé: | University of Zurich, Knuesel, Irene |
| Rok vydání: | 2012 |
| Předmět: |
Male
Neurons Extracellular Matrix Proteins Protein Folding Cell Adhesion Molecules Neuronal Serine Endopeptidases 10050 Institute of Pharmacology and Toxicology 2800 General Neuroscience 610 Medicine & health Nerve Tissue Proteins Hippocampus Mice Inbred C57BL Mice Reelin Protein Poly I-C nervous system Pregnancy Prenatal Exposure Delayed Effects Microscopy Electron Scanning 570 Life sciences biology Animals Female Microscopy Immunoelectron Neuroglia Cellular Senescence |
| Zdroj: | The European journal of neuroscience |
| DOI: | 10.5167/uzh-74256 |
| Popis: | Cellular senescence is the consequence of repetitive exposures to oxidative stress, perturbed energy homeostasis, accumulation of damaged proteins and lesions in their nucleic acids. Whereas mitotic cells are equipped with efficient cell replacement strategies; postmitotic neurons have--with a few exceptions--no mechanism to substitute dysfunctional cells within a complex neuronal network. Here we propose a potential strategy by which aging neurons contend against abnormal accumulation of damaged/misfolded proteins. The suggested mechanism involves the formation of 'budding-like' extrusions and their subsequent clearance by glia. This hypothesis emerged from our previous investigations of the aged hippocampus revealing layer-specific accumulations of Reelin, a glycoprotein with fundamental roles during brain development and adult synaptic plasticity. We showed that Reelin deposits constitute a conserved neuropathological feature of aging, which is significantly accelerated in adult wild-type mice prenatally exposed to a viral-like infection. Here, we employed two- and three-dimensional immunoelectron microscopy to elucidate their morphological properties, localization and origin in immune challenged vs. control mice. In controls, Reelin-positive deposits were dispersed in the neuropil, some being engulfed by glia. In immune challenged mice, however, significantly more Reelin-immunoreactive deposits were associated with neuritic swellings containing mitochondria, vacuoles and cellular debris, pointing to their intracellular origin and suggesting that 'budding-like' neuronal extrusions of misfolded proteins and glial clearance may represent a protective strategy to counteract aging-associated impairments in proteosomal/lysosomal degradation. Neurons exposed to chronic neuroinflammation with increased levels of misfolded/damaged proteins, however, may fail to combat intraneuronal protein accumulations, a process probably underlying neuronal dysfunction and degeneration during aging. |
| Databáze: | OpenAIRE |
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