Missense mutations in the gene encoding copper zinc superoxide dismutase (SOD1) have been found to cause one form of familial amyotrophic lateral sclerosis (FALS).
The aim of this study is to determine the effects of hNT Neuron transplants on motor neuron function in a mouse model of familial amyotrophic lateral sclerosis (FALS) in which there is a substitution of Alanine for Glycine at position 93 of the human SOD1 gene (G93A).
These results suggest that peripheral targets such as hindlimb skeletal muscle and nerve accumulate mutant SOD1 aggregates and may therefore be susceptible to mutant SOD1-mediated toxicity, in addition to lower and upper motor neurons of the central nervous system in transgenic FALS mice.
Mutations in the Cu/Zn superoxide dismutase 1 (SOD1) gene have been reported to cause adult-onset autosomal dominant amyotrophic lateral sclerosis (FALS).
Recent work has demonstrated that a portion of mutant SOD1 is localized in mitochondria, both in transgenic mice and in FALS patients, where it forms proteinaceous aggregates.
We previously reported on a FALS family whose members had a mutant form of SOD1 characterized by a 2-base pair (bp) deletion at codon 126 of the SOD1 gene.
However, the patient has no Lewy body-like hyaline inclusions (LBHIs), which are characteristic features of mutant SOD1-related FALS with posterior column involvement.
Neuronal Lewy body-like hyaline inclusions (LBHI) and astrocytic hyaline inclusions (Ast-HI) are morphological hallmarks of certain familial amyotrophic lateral sclerosis (FALS) patients with superoxide dismutase-1 (SOD1) gene mutations, and transgenic mice expressing the human SOD1 gene mutation.
We analyzed mutant superoxide dismutase-1 (SOD-1) in erythrocytes from patients with familial amyotrophic lateral sclerosis (FALS) by using ion exchange chromatography and HPLC/electrospray ionization mass spectrometry and were able to divide mutant SOD-1 proteins into a stable form including G37R and H46R, and an unstable form including I149T and a two base pair deletion mutant.
These results suggest that oxidative damage inhibits the degradation of FALS-related mutant human SOD1 proteins, resulting in an aberrant accumulation of mutant proteins that might contribute to the cytotoxicity.
These results suggest that the Ala4Thr mutation in SOD1 decreases the stability of SOD1 and that this instability may play an important role in the pathogenesis of the degeneration of motor neurons in FALS.
Superoxide dismutase 1 (SOD1) proteins harboring mutations linked to familial amyotrophic lateral sclerosis (FALS) uniformly show heightened potential to form high molecular weight structures.
In SOD1-mutated FALS patients, Lewy body-like hyaline inclusions (LBHIs) in some residual anterior horn cells exhibited co-aggregation of both HGF and c-Met, although the cytoplasmic staining intensity for HGF and c-Met in the LBHI-bearing neurons was either weak or negative.
Introduction of human wild type SOD1 (hWT-SOD1) gene, which does not cause motor impairment by itself, into different FALS mice resulted in different effects on their clinical courses, from no effect in G85R-mice to acceleration of disease progression in G93A-mice.
Based on the temporal correlation of these impairments with the onset of motor weakness and the appearance of NF inclusions and vacuoles in vulnerable motor neurons, the latter lesions may be the proximal cause of motor neuron dysfunction and degeneration in the G93A mice and in FALS patients with SOD1 mutations.
We have identified a new mutant Cu/Zn superoxide dismutase (SOD1) deduced from the nucleotide sequences of peripheral blood lymphocyte mRNA from Japanese patients with familial amyotrophic lateral sclerosis (FALS).