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An immunological epitope selective for pathological monomer-misfolded SOD1 in ALS.

Abstract：

:Misfolding of Cu/Zn-superoxide dismutase (SOD1) is emerging as a mechanism underlying motor neuron degeneration in individuals with amyotrophic lateral sclerosis (ALS) who carry a mutant SOD1 gene (SOD1 ALS). Here we describe a structure-guided approach to developing an antibody that specifically recognizes monomer-misfolded forms of SOD1. We raised this antibody to an epitope that is normally buried in the SOD1 native homodimer interface. The SOD1 exposed dimer interface (SEDI) antibody recognizes only those SOD1 conformations in which the native dimer is disrupted or misfolded and thereby exposes the hydrophobic dimer interface. Using the SEDI antibody, we established the presence of monomer-misfolded SOD1 in three ALS mouse models, with G37R, G85R and G93A SOD1 mutations, and in a human individual with an A4V SOD1 mutation. Despite ubiquitous expression, misfolded SOD1 was found primarily within degenerating motor neurons. Misfolded SOD1 appeared before the onset of symptoms and decreased at the end stage of the disease, concomitant with motor neuron loss.

journal_name

Nat Med

journal_title

Nature medicine

authors

Rakhit R,Robertson J,Vande Velde C,Horne P,Ruth DM,Griffin J,Cleveland DW,Cashman NR,Chakrabartty A

doi

10.1038/nm1559

subject

Has Abstract

pub_date

2007-06-01 00:00:00

pages

754-9

issue

6

eissn

1078-8956

issn

1546-170X

pii

nm1559

journal_volume

13

pub_type

杂志文章

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