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Assay Development for High Content Quantification of Sod1 Mutant Protein Aggregate Formation in Living Cells
Published on: October 4, 2017
Mechanisms of mutant SOD1 induced mitochondrial toxicity in amyotrophic lateral sclerosis
Piia Vehviläinen1, Jari Koistinaho1, Goldsteins Gundars1
1Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland Kuopio, Finland.
Abstract:
In amyotrophic lateral sclerosis (ALS), mitochondrial dysfunction is recognized as one of the key elements contributing to the pathology. Mitochondria are the major source of intracellular reactive oxygen species (ROS). Increased production of ROS as well as oxidative damage of proteins and lipids have been demonstrated in many models of ALS. Moreover, these changes were also observed in tissues of ALS patients indicative of important role for oxidative stress in the disease pathology. However, the origin of oxidative stress in ALS has remained unclear. ALS linked mutant Cu/Zn-superoxide dismutase 1 (SOD1) has been shown to significantly associate with mitochondria, especially in the spinal cord. In animal models, increased recruitment of mutant SOD1 (mutSOD1) to mitochondria appears already before the disease onset, suggestive of causative role for the manifestation of pathology. Recently, substantial in vitro and in vivo evidence has accumulated demonstrating that localization of mutSOD1 to the mitochondrial intermembrane space (IMS) inevitably leads to impairment of mitochondrial functions. However, the exact mechanisms of the selectivity and toxicity have remained obscure. Here we discuss the current knowledge on the role of mutSOD1 in mitochondrial dysfunction in ALS from the novel perspective emphasizing the misregulation of dismutase activity in IMS as a major mechanism for the toxicity.
Insights
Mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS) is linked to mutant Cu/Zn-superoxide dismutase 1 (SOD1). Misregulation of SOD1 activity within mitochondria contributes to disease progression.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Mitochondrial dysfunction is a key factor in amyotrophic lateral sclerosis (ALS) pathology.
- Oxidative stress, indicated by increased reactive oxygen species (ROS) and damage, is observed in ALS patients and models.
- The precise origin of oxidative stress in ALS has remained unclear.
Purpose of the Study:
- To explore the role of mutant Cu/Zn-superoxide dismutase 1 (mutSOD1) in mitochondrial dysfunction in ALS.
- To investigate the mechanisms by which mutSOD1 contributes to ALS pathology.
- To highlight the misregulation of SOD1 activity in the mitochondrial intermembrane space (IMS) as a key toxic mechanism.
Main Methods:
- Review of current in vitro and in vivo evidence on mutSOD1 and mitochondrial function.
- Analysis of the association of mutSOD1 with mitochondria in ALS models and patients.
- Discussion of the localization and activity of mutSOD1 within the mitochondrial intermembrane space.
Main Results:
- Mutant SOD1 (mutSOD1) significantly associates with mitochondria in ALS, particularly in the spinal cord.
- Increased recruitment of mutSOD1 to mitochondria precedes disease onset in animal models.
- Localization of mutSOD1 to the mitochondrial intermembrane space (IMS) impairs mitochondrial functions.
Conclusions:
- Misregulation of dismutase activity of SOD1 within the mitochondrial IMS is a major mechanism of toxicity in ALS.
- Mutant SOD1's interaction with mitochondria is a critical factor in ALS pathogenesis.
- Understanding mutSOD1's role in mitochondrial dysfunction offers novel therapeutic perspectives for ALS.
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