Amyotrophic lateral sclerosis: A proposed mechanism

Missense mutations in Cu,Zn-superoxide dismutase (SOD1) account for ≈20% of familial amyotrophic lateral sclerosis (FALS) through some, as yet undefined, toxic gain of function that leads to gradual death of motor neurons. Mitochondrial swelling and vacuolization are early signs of incipient motor neuron death in FALS. We previously reported that SOD1 exists in the intermembrane space of mitochondria. Herein, we demonstrate that the entry of SOD1 into mitochondria depends on demetallation and that heat shock proteins (Hsp70, Hsp27, or Hsp25) block the uptake of the FALS-associated mutant SOD1 (G37R, G41D, or G93A), while having no effect on wild-type SOD1. The binding of mutant SOD1 to Hsps in the extract of neuroblastoma cells leads to formation of sedimentable aggregates. Many antiapoptotic effects of Hsps have been reported. We now propose that this binding of Hsps to mutant forms of a protein abundant in motor neurons, such as SOD1, makes Hsps unavailable for their antiapoptotic functions and leads ultimately to motor neuron death. It also appears that the Hsp–SOD1 complex recruits other proteins present in the neuroblastoma cell and presumably in motor neurons to form sedimentable aggregates.

[1]  O. Steward,et al.  Zn2+ Induces Permeability Transition Pore Opening and Release of Pro-apoptotic Peptides from Neuronal Mitochondria* , 2001, The Journal of Biological Chemistry.

[2]  C. Tohyama,et al.  Stabilization of mutant Cu/Zn superoxide dismutase (SOD1) protein by coexpressed wild SOD1 protein accelerates the disease progression in familial amyotrophic lateral sclerosis mice , 2001, The European journal of neuroscience.

[3]  I. Fridovich,et al.  Subcellular Distribution of Superoxide Dismutases (SOD) in Rat Liver , 2001, The Journal of Biological Chemistry.

[4]  L. T. Jensen,et al.  A fraction of yeast Cu,Zn-superoxide dismutase and its metallochaperone, CCS, localize to the intermembrane space of mitochondria. A physiological role for SOD1 in guarding against mitochondrial oxidative damage. , 2001, The Journal of biological chemistry.

[5]  J. Holstege,et al.  CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations , 2001, Acta Neuropathologica.

[6]  Josef M. Penninger,et al.  Heat-shock protein 70 antagonizes apoptosis-inducing factor , 2001, Nature Cell Biology.

[7]  G. Kroemer,et al.  Heat shock proteins: endogenous modulators of apoptotic cell death. , 2001, Biochemical and biophysical research communications.

[8]  Manisha N. Patel,et al.  Dependence of excitotoxic neurodegeneration on mitochondrial aconitase inactivation , 2001, Journal of neurochemistry.

[9]  S. Minotti,et al.  Mutant Cu/Zn-Superoxide Dismutase Proteins Have Altered Solubility and Interact with Heat Shock/Stress Proteins in Models of Amyotrophic Lateral Sclerosis* , 2001, The Journal of Biological Chemistry.

[10]  J. Julien,et al.  Amyotrophic Lateral Sclerosis Unfolding the Toxicity of the Misfolded , 2001, Cell.

[11]  Guido Kroemer,et al.  Hsp27 negatively regulates cell death by interacting with cytochrome c , 2000, Nature Cell Biology.

[12]  W. Markesbery,et al.  Decreased levels of proteasome activity and proteasome expression in aging spinal cord , 2000, Neuroscience.

[13]  W. Koppenol,et al.  The preparation of apo-Cu,Zn superoxide dismutase by ion-exchange chromatography on iminodiacetic acid-sepharose. , 2000, Protein expression and purification.

[14]  D. Rubinsztein,et al.  Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[15]  E. Solary,et al.  HSP27 inhibits cytochrome c‐dependent activation of procaspase‐9 , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[16]  Wendy Bruening,et al.  Up‐Regulation of Protein Chaperones Preserves Viability of Cells Expressing Toxic Cu/Zn‐Superoxide Dismutase Mutants Associated with Amyotrophic Lateral Sclerosis , 1999, Journal of neurochemistry.

[17]  D. Borchelt,et al.  Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[18]  S. Korsmeyer,et al.  Regulated Targeting of BAX to Mitochondria , 1998, The Journal of cell biology.

[19]  I. Fridovich,et al.  Superoxide-dependent peroxidase activity of H48Q: a superoxide dismutase variant associated with familial amyotrophic lateral sclerosis. , 1997, Archives of biochemistry and biophysics.

[20]  Eva Mezey,et al.  Mutations in SOD1 associated with amyotrophic lateral sclerosis cause novel protein interactions , 1997, Nature Genetics.

[21]  E. K. Hoffman,et al.  Proteasome inhibition enhances the stability of mouse Cu Zn superoxide dismutase with mutations linked to familial amyotrophic lateral sclerosis , 1996, Journal of the Neurological Sciences.

[22]  M. Gurney,et al.  Benefit of vitamin E, riluzole, and gababapentin in a transgenic model of familial amyotrophic lateral sclerosis , 1996, Annals of neurology.

[23]  D. Borchelt,et al.  Superoxide dismutase is an abundant component in cell bodies, dendrites, and axons of motor neurons and in a subset of other neurons. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[24]  S. Bondy,et al.  The relationship between excitotoxicity and oxidative stress in the central nervous system. , 1993, Free radical biology & medicine.

[25]  W. Welch,et al.  Morphological study of the mammalian stress response: characterization of changes in cytoplasmic organelles, cytoskeleton, and nucleoli, and appearance of intranuclear actin filaments in rat fibroblasts after heat-shock treatment , 1985, The Journal of cell biology.