Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis.
The occurrence of endoplasmic reticulum (ER) stress in the sporadic form of amyotrophic lateral sclerosis (ALS) is unknown, despite it has been recently documented in experimental models of the familial form. Here we show that spinal cord from patients with sporadic ALS showed signs of ER stress, such as increased levels of ER chaperones such as protein-disulfide isomerase, and increased phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha). Among the potential causes of such ER stress proteasomal impairment was confirmed in the same samples by demonstrating increased ubiquitin immunoreactivity and increased protein lipoxidative (125%), glycoxidative (55%) and direct oxidative damage (62%) over control values, as evidenced by mass-spectrometry and immunological methods. We found that protein oxidative damage was strongly associated to ALS-specific changes in fatty acid concentrations, specifically of n-3 series (as docosahexaenoic acid), and in the amount of mitochondrial components as respiratory complexes I and III, suggesting a mitochondrial dysfunction leading to increased free radical production. Oxidative stress was also evidenced in frontal cortex, suggesting that this region is affected early in ALS. As those events were partially reproduced by threohydroxyaspartate exposure in organotypic spinal cord cultures, we concluded that changes in fatty acid composition, mitochondrial function and proteasome activity, which may be driven by excitotoxicity, lead to oxidative stress and finally contribute to ER stress in sporadic ALS.
Ilieva
Ekaterina V
EV
Fisiopatologia Metabòlica, IRBLLEIDA, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida, Lleida, Spain.
Ayala
Victòria
V
Jové
Mariona
M
Dalfó
Esther
E
Cacabelos
Daniel
D
Povedano
Mónica
M
Bellmunt
Maria Josep
MJ
Ferrer
Isidre
I
Pamplona
Reinald
R
Portero-Otín
Manuel
M
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000503:physiopathology*; D004721:Endoplasmic Reticulum / Q000502:physiology*; D005227:Fatty Acids / Q000032:analysis; D005260:Female; D005625:Frontal Lobe / Q000737:chemistry; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000737:chemistry; D009924:Organ Culture Techniques; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D013116:Spinal Cord / Q000737:chemistry / Q000503:physiopathology; D025801:Ubiquitin / Q000378:metabolism
D005227:Fatty Acids; D009419:Nerve Tissue Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex