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Calcium dysregulation, mitochondrial pathology and protein aggregation in a culture model of amyotrophic lateral sclerosis: Mechanistic relationship and differential sensitivity to intervention
- Source :
- Neurobiology of Disease, Vol 42, Iss 3, Pp 265-275 (2011)
- Publication Year :
- 2011
- Publisher :
- Elsevier, 2011.
-
Abstract
- The combination of Ca(2+) influx during neurotransmission and low cytosolic Ca(2+) buffering contributes to the preferential vulnerability of motor neurons in amyotrophic lateral sclerosis (ALS). This study investigated the relationship among Ca(2+) accumulation in intracellular compartments, mitochondrial abnormalities, and protein aggregation in a model of familial ALS (fALS1). Human SOD1, wild type (SOD1(WT)) or with the ALS-causing mutation G93A (SOD1(G93A)), was expressed in motor neurons of dissociated murine spinal cord-dorsal root ganglia (DRG) cultures. Elevation of mitochondrial Ca(2+) ([Ca(2+)](m)), decreased mitochondrial membrane potential (Δψ) and rounding of mitochondria occurred early, followed by increased endoplasmic reticular Ca(2+) ([Ca(2+)](ER)), elevated cytosolic Ca(2+) ([Ca(2+)](c)), and subsequent appearance of SOD1(G93A) inclusions (a consequence of protein aggregation). [Ca(2+)](c) was elevated to a greater extent in neurons with inclusions than in those with diffusely distributed SOD1(G93A) and promoted aggregation of mutant protein, not vice versa: both [Ca(2+)](c) and the percentage of neurons with SOD1(G93A) inclusions were reduced by co-expressing the cytosolic Ca(2+)-buffering protein, calbindin D-28K; treatment with the heat shock protein inducer, geldanamycin, prevented inclusions but not the increase in [Ca(2+)](c), [Ca(2+)](m) or loss of Δψ, and inhibiting proteasome activity with epoxomicin, known to promote aggregation of disease-causing mutant proteins including SOD1(G93A), had no effect on Ca(2+) levels. Both expression of SOD1(G93A) and epoxomicin-induced inhibition of proteasome activity caused mitochondrial rounding, independent of Ca(2+) dysregulation and reduced Δψ. That geldanamycin prevented inclusions and mitochondrial rounding, but not Ca(2+) dysregulation or loss of Δψ indicates that chaperone-based therapies to prevent protein aggregation may require co-therapy to address these other underlying mechanisms of toxicity.
- Subjects :
- Proteasome Endopeptidase Complex
Motor neuron
SOD1
Protein aggregation
Biology
Mitochondrion
lcsh:RC321-571
Mice
chemistry.chemical_compound
Superoxide Dismutase-1
Epoxomicin
Mutant protein
Animals
Amyotrophic lateral sclerosis (ALS)
lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
Cells, Cultured
Membrane Potential, Mitochondrial
Motor Neurons
Microscopy, Confocal
Proteasome
Superoxide Dismutase
Endoplasmic reticulum
Amyotrophic Lateral Sclerosis
Geldanamycin
Cell biology
Mitochondria
Disease Models, Animal
Cytosol
Spinal Cord
Neurology
chemistry
Biochemistry
Calcium
Subjects
Details
- Language :
- English
- Volume :
- 42
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Neurobiology of Disease
- Accession number :
- edsair.doi.dedup.....1a64a665f90723c5fe8d815fc5795d0d