. Mutant superoxide dismutase 1 forms aggregates in the brain mitochondrial matrix of amyotrophic lateral sclerosis mice. J Neurosci. 2005 Mar 9;25(10):2463-70. PubMed.


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  1. Mitochondria: Another Dimension in Protein Misfolding
    A growing body of evidence indicates that mitochondrial abnormalities play an important role in the development of neurodegenerative diseases. In addition, mitochondrial abnormalities appear to be a central target in the development and maturation of neurodegeneration, specifically, Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). Recent work from our laboratories demonstrated that mitochondrial abnormality indeed appears to be a primary target for brain damage as a surrogate for amyloid deposition, as is seen in human AD and transgenic mouse models of AD.

    Recent findings by Vijayvergiya and coworkers demonstrated that a mutant form of superoxide dismutase 1 forms aggregates in the brain mitochondrial matrix of amyotrophic lateral sclerosis mice. Because SOD1 is largely a cytosolic protein, it is shuttled to the mitochondria. A portion of SOD1 is localized in the mitochondria of patients with familial amyotrophic lateral sclerosis (FALS) as well as in a transgenic mouse model of the disease. This study is the first to demonstrate that both wild-type and mutant human SOD1 accumulate in brain mitochondria of transgenic mice, and reveals a very complex intramitochondrial compartmentalization, including accumulation of SOD1 in the mitochondrial matrix.

    Most of the observations in this study have been characterized using densitometry of Western blots, especially the analysis of misfolded SOD1. Since the mitochondria shuttle most of their proteins from the cytosol after synthesis on ribosomes, misfolded proteins are normally refolded, for example, by PDI or chaperone proteins, and, if proteins remain improperly folded or aggregated, they never leave the endoplasmic reticulum (ER) to reach their target, but are degraded. Thus, the misfolded proteins found in this study should be degraded rather than transported into the Golgi complex or to the ER. Therefore, the finding of misfolded proteins in the mitochondria is an important observation. However, further characterization of this finding is needed, as well as the sequence of events leading to this occurrence.

    We believe that altered metal binding also may be a major contributor to mutant SOD1 aggregation in the mitochondrial matrix. Expanding the research in this model to include characterization of the folding of this SOD1 mutant by circular dichroism and by using cytological detection of SOD1 isoform expression and localization at the electron microscopic level would be very helpful to determine the nature of the protein folding defect and its relationship to the mitochondria. This new direction may shed light on many questions regarding the role of mitochondrial abnormalities in the development of neurodegeneration. Expanding research in the area of mitochondria protein misfolding may open new treatment strategy opportunities for these devastating diseases.

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