Selective knockdown of misfolded SOD1 as a therapy for amyotrophic lateral sclerosis

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Zhou, Ting
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that features progressive degeneration of motor neurons. Over the past two decades, a major breakthrough in ALS research is the discovery that mutations in the gene superoxide dismutase 1 (SOD1) are a cause of familial ALS (fALS). Strong evidence supports that the fFALS-linked SOD1 variants are readily susceptible to posttranslational modifications, and subsequently become misfolded. Accumulation of the misfolded SOD1 triggers a toxic cascade leading to motor neuron degeneration. Studies also show that the wild type (WT) human SOD1, when modified post-translationally, undergoes aberrant conformational changes and acquires the same toxic properties that are observed in fALS-associated SOD1 variants. Misfolded SOD1 is thus at the center of ALS pathogenesis and a common toxic factor to a subset of both familial and sporadic ALS. Targeting misfolded SOD1 is therefore a rational approach towards an effective treatment for ALS. Here I present a new approach to selectively knockdown misfolded SOD1 by insertion of the CT-4 epitope of Derlin-1 into the chaperone-mediated autophagy system (CMA). In this study, I report efficiency and specificity of CT-4 peptide in knocking down misfolded SOD1 in vitro and in vivo. Our results revealed that CT-4 treatment resulted in a selective degradation of misfolded SOD1 in a dose-, time- and lysosomal activity-dependent manner in vitro. The in vivo studies revealed that CT-4 treatment resulted in knockdown of misfolded SOD1 in the tissues from the G93A transgenic mouse model of ALS. In addition, daily injection of CT-4 peptide significantly attenuated loss of motor neurons, delayed disease onset and extended lifespan of G93A transgenic mice of ALS. Furthermore, I explored the potential mechanisms underlying which CT-4 peptide delayed disease onset. My data indicated that knockdown of misfolded SOD1 could directly affect monocarboxylate transporter 1 (MCT1) protein expression in spinal cord, suggesting that CT-4 peptide treatment could result in preservation of MCT1 expression, maintenance of axon myelin and protection of neurons in ALS animal model. Therefore, the peptide may be developed into an effective treatment for ALS.
Amyotrophic lateral sclerosis (ALS), Misfolded SOD1, Chaperone mediated autophagy, CT-4 peptide