For Manuscript Submission, Check or Review Login please go to Submission Websites List.
For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.
Mutant SOD1 Instability: Implications for Toxicity in Amyotrophic Lateral SclerosisTiwari A. · Hayward L.J.
Department of Neurology, University of Massachusetts Medical School, Worcester, Mass., USA
The biological basis of preferential motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remains incompletely understood, and effective therapies to prevent the lethal consequences of this disorder are not yet available. Since 1993, more than 100 mutant variants of the antioxidant enzyme Cu/Zn superoxide dismutase (SOD1) have been identified in familial ALS. Many studies have sought to distinguish abnormal properties shared by these proteins that may contribute to their toxic effects and cause age-dependent motor neuron loss. Complex networks of cellular interactions and changes associated with aging may link mutant SOD1s and other stresses to motor neuron death in ALS. Our laboratory and collaborators have compared physicochemical properties of biologically metallated wild-type and mutant SOD1 proteins to discern specific vulnerabilities that may be relevant to the mutant toxicity in vivo. X-ray crystal structures obtained from metallated ‘wild-type-like’ (WTL) SOD1 mutants, which retain the ability to bind copper and zinc and exhibit normal specific activity, indicate a native-like structure with only subtle changes to the backbone fold. In contrast, a group of ‘metal-binding region’ (MBR) SOD1 mutants that are deficient in copper and zinc exhibit severe thermal destabilization and structural disorder of conserved loops near the metal-binding sites. A growing body of evidence highlights specific stresses in vivo that may perturb well-folded, metallated SOD1 variants and thereby favor an increased burden of partially unfolded, metal-deficient species. For example, WTL SOD1 mutants are more susceptible than wild-type SOD1 to reduction of the intrasubunit disulfide bond between Cys-57 and Cys-146 at physiological pH and temperature. This bond anchors the disulfide loop to the SOD1 β-barrel and helps to maintain the dimeric configuration of the protein. Cleavage of the disulfide linkage renders the well-folded WTL mutants vulnerable to metal loss and monomerization such that they may resemble the destabilized and locally misfolded MBR mutant species. SOD1 proteins with disordered loops or monomeric structure are expected to be more susceptible to aberrant self-association or detrimental interactions with other cellular constituents. The challenge for future investigations is to relate these abnormal properties of partially unfolded SOD1 to specific mechanisms of toxicity in motor neurons, supporting cells, or target tissues.
© 2005 S. Karger AG, Basel