Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation

Abstract

Mutations in the gene encoding the ubiquitously expressed free radical scavenging enzyme superoxide dismutase-1 (SOD1) are found in 2–6% of amyotrophic lateral sclerosis patients. The most frequent SOD1 mutation worldwide is D90A. Amyotrophic lateral sclerosis caused by this mutation has some unusual features: the heredity is usually recessive, the phenotype is stereotypic with slowly evolving motor symptoms beginning in the legs and may also include sensory, autonomic, and urinary bladder involvement. Furthermore, the mutant protein resembles the wild type, with normal content and enzymatic activity in the central nervous system. Here, we report neuropathological findings in nine patients homozygous for the D90A mutation. All nine had numerous small granular inclusions immunoreactive for misfolded SOD1 in motor neurons and glial nuclei in the spinal cord and brainstem. In addition to degeneration of the corticospinal tracts, all patients had degeneration of the dorsal columns. We also found intense gliosis in circumscribed cortical areas of the frontal and temporal lobes and in the insula. In these areas and in adjacent white matter, there were SOD1 staining neuropil threads. A few SOD1-immunopositive cytoplasmic neuronal inclusions were observed in cortical areas, as were glial nuclear inclusions. As suggested by the symptoms and signs and earlier neurophysiological and imaging investigations, the histopathology in patients homozygous for the D90A SOD1 extends beyond the motor system to include cognitive and sensory cortical areas. However, even in the patients that had a symptomatic disease duration of more than 2 or 3 decades and lived into their 70s or 80s, there were no SOD1-inclusion pathology and no typical dysfunction (apart from the musculature) in non-nervous organs. Thus, only specific parts of the CNS seem to be vulnerable to toxicity provoked by homozygously expressed mutant SOD1.

ALS-causing SOD1 mutations H46R and G85R form similar novel amyloid fibril structures and promote ferroptosis in cells

“…Mutations in SOD1 account for about 2−6% of all ALS 1,2,14−16, 56 . Because familial mutations in SOD1, such as H46R and G85R, are involved in the pathogenesis of the motor neuron disease ALS where it is observed to form intracellular fibrillar inclusions 3,14,20,32,33,35,57 , it has generally been thought that these proteinaceous inclusions could be responsible for neuronal cell death in patients with ALS 3,14,35 .…”

Disorders of Endogenous and Exogenous Antioxidants in Neurological Diseases

“…It has high affinity for heparin and heparin sulfates [17,18]. It is also expressed in the CNS but at lower concentrations than SOD1 and SOD2 [19,20].…”