Endoplasmic Reticulum Stress in Motor Neurons of the Spinal Cord in Sporadic Amyotrophic Lateral Sclerosis

The accumulation of misfolded or unfolded proteins in the endoplasmic reticulum (ER) lumen causes a cellular stress response termed the unfolded protein response. Although ER stress has been implicated in various neurodegenerative diseases, the morphological features of aggregated proteins in ER lum...

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Bibliographic Details
Published in:Journal of neuropathology and experimental neurology 2010-04, Vol.69 (4), p.346-355
Main Author: Sasaki, Shoichi
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Amyotrophic Lateral Sclerosis - pathology
Biological and medical sciences
Case-Control Studies
Diseases of the nervous system
Endoplasmic Reticulum - metabolism
Female
Heat-Shock Proteins - metabolism
Humans
Male
Medical sciences
Middle Aged
Motor Neurons - metabolism
Motor Neurons - ultrastructure
Neurology
Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects)
Spinal Cord - pathology
Ubiquitin - metabolism
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Summary:The accumulation of misfolded or unfolded proteins in the endoplasmic reticulum (ER) lumen causes a cellular stress response termed the unfolded protein response. Although ER stress has been implicated in various neurodegenerative diseases, the morphological features of aggregated proteins in ER lumina that may cause neurodegeneration have not been well characterized. We examined anterior horn neurons using immunohistochemistry and electron microscopy in12 sporadic amyotrophic lateral sclerosis (ALS) patients and 12 controls. Approximately 2.6% of both normal-appearing and degenerated motor neurons in ALS cases were immunostained for the ER chaperone protein glucose-regulated protein 78, and approximately 0.1% of these neurons was glucose-regulated protein 78 positive incontrols (p = 0.0004). Amyotrophic lateral sclerosis cases also tended to have glucose-regulated protein 78-positive motor neurons more frequently than control cases (p = 0.08). By electron microscopy,neurons in ALS patients showed accumulations of amorphous and granularmaterial suggestive of misfolded or unfolded proteins indilated predominantly normal-appearing ER. There were also wavymembranous structures extending from the ER membranes that lacked membrane-bound ribosomes, electron-dense material resembling Bunina bodies, Hirano bodies, honeycomb-like structures, and membrane-particle complexes associated with the ER in these neurons. Control sample neurons demonstrated none of these features. These ERalterations suggest that the unfolded protein response is activated inmotor neurons in ALS patients and provide the first morphologicalevidence that ER stress may be involved in the neurodegeneration of motor neurons in early stages of sporadic ALS.
ISSN:0022-3069
1554-6578
DOI:10.1097/NEN.0b013e3181d44992