Transgenic mice with human mutant genes causing Parkinson's disease and amyotrophic lateral sclerosis provide common insight into mechanisms of motor neuron selective vulnerability to degeneration

Research output: Contribution to journalReview articlepeer-review

Abstract

A variety of gene mutations can cause familial forms of Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS). Mutations in the synaptic protein α-synuclein (α-Syn) cause PD. Mutations in the antioxidant enzyme superoxide dismutase-1 (SOD1) cause ALS. The mechanisms of human mutant α-Syn and SOD1 toxicity to neurons are not known. Transgenic (tg) mice expressing human mutant α-Syn or SOD1 develop profound fatal neurologic disease characterized by progressive motor deficits, paralysis, and neurodegeneration. Ala-53→Thr (A53T)-mutant α-Syn and Gly-93→Ala (G93A)-mutant SOD1 tg mice develop prominent mitochondrial abnormalities. Interestingly, although nigral neurons in A53T mice are relatively preserved, spinal motor neurons (MNs) undergo profound degeneration. In A53T mice, mitochondria degenerate in neurons, and complex IV activity is reduced. Furthermore, mitochondria in neurons develop DNA breaks and have p53 targeted to the outer membrane. Nitrated α-Syn accumulates in degenerating MNs in A53T mice. mSOD1 mouse MNs accumulate mitochondria from the axon terminals and generate higher levels of reactive oxygen/nitrogen species than MNs in control mice. mSOD1 mouse MNs accumulate DNA single-strand breaks prior to double-strand breaks occurring in nuclear and mitochondrial DNA. Nitrated and aggregated cytochrome c oxidase subunit-I and nitrated SOD2 accumulate in mSOD1 mouse spinal cord. Mitochondria in mSOD1 mouse MNs accumulate NADPH diaphorase and inducible NOS (iNOS)-like immunoreactivity, and iNOS gene deletion significantly extends the lifespan of G93A-mSOD1 mice. Mitochondrial changes develop long before symptoms emerge. These experiments reveal that mitochondrial nitrative stress and perturbations in mitochondrial trafficking may be antecedents of neuronal cell death in animal models of PD and ALS.

Original languageEnglish (US)
Pages (from-to)115-136
Number of pages22
JournalReviews in the Neurosciences
Volume18
Issue number2
DOIs
StatePublished - 2007

Keywords

  • Apoptosis
  • DNA damage
  • Mitochondria
  • Peroxynitrite
  • iNOS
  • p53
  • α-synuclein

ASJC Scopus subject areas

  • Neuroscience(all)

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