Motor neuron degeneration in amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice: Mechanisms of mitochondriopathy and cell death
Corresponding Author
Lee J. Martin
Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196
Johns Hopkins University School of Medicine, Department of Pathology, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196Search for more papers by this authorZhiping Liu
Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196
Search for more papers by this authorKevin Chen
Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196
Search for more papers by this authorAnn C. Price
Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196
Search for more papers by this authorYan Pan
Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196
Search for more papers by this authorJason A. Swaby
Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196
Search for more papers by this authorW. Christopher Golden
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196
Search for more papers by this authorCorresponding Author
Lee J. Martin
Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196
Johns Hopkins University School of Medicine, Department of Pathology, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196Search for more papers by this authorZhiping Liu
Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196
Search for more papers by this authorKevin Chen
Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196
Search for more papers by this authorAnn C. Price
Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196
Search for more papers by this authorYan Pan
Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196
Search for more papers by this authorJason A. Swaby
Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196
Search for more papers by this authorW. Christopher Golden
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196
Search for more papers by this authorAbstract
The mechanisms of human mutant superoxide dismutase-1 (mSOD1) toxicity to motor neurons (MNs) are unresolved. We show that MNs in G93A-mSOD1 transgenic mice undergo slow degeneration lacking similarity to apoptosis structurally and biochemically. It is characterized by somal and mitochondrial swelling and formation of DNA single-strand breaks prior to double-strand breaks occurring in nuclear and mitochondrial DNA. p53 and p73 are activated in degenerating MNs, but without nuclear import. The MN death is independent of activation of caspases-1, -3, and -8 or apoptosis-inducing factor within MNs, with a blockade of apoptosis possibly mediated by Aven up-regulation. MN swelling is associated with compromised Na,K-ATPase activity and aggregation. mSOD1 mouse MNs accumulate mitochondria from the axon terminals and generate higher levels of superoxide, nitric oxide, and peroxynitrite than MNs in control mice. Nitrated and aggregated cytochrome c oxidase subunit-I and α-synuclein as well as nitrated SOD2 accumulate in mSOD1 mouse spinal cord. Mitochondria in mSOD1 mouse MNs accumulate NADPH diaphorase and inducible nitric oxide synthase (iNOS)-like immunoreactivity, and iNOS gene deletion extends significantly the life span of G93A-mSOD1 mice. Prior to MN loss, spinal interneurons degenerate. These results identify novel mechanisms for mitochondriopathy and MN degeneration in amyotrophic lateral sclerosis (ALS) mice involving blockade of apoptosis, accumulation of MN mitochondria with enhanced toxic potential from distal terminals, NOS localization in MN mitochondria and peroxynitrite damage, and early degeneration of α-synuclein+ interneurons. The data support roles for oxidative stress, protein nitration and aggregation, and excitotoxicity as participants in the process of MN degeneration caused by mSOD1. J. Comp. Neurol. 500:20–46, 2007. © 2006 Wiley-Liss, Inc.
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