OBJECTIVE

A hallmark of amyotrophic lateral sclerosis (ALS) caused by mutations in () are inclusions containing SOD1 in motor neurons. Here, we searched for SOD1-positive inclusions in 29 patients carrying ALS-linked mutations in six other genes.

METHODS

A panel of antibodies that specifically recognise misfolded SOD1 species were used for immunohistochemical investigations of autopsy tissue.

RESULTS

The 18 patients with hexanucleotide-repeat-expansions in had inclusions of misfolded wild type (WT) SOD1 in spinal motor neurons. Similar inclusions were occasionally observed in medulla oblongata and in the motor cortex and frontal lobe. Patients with mutations in or , carried similar SOD1 inclusions. Minute amounts of misSOD1 inclusions were detected in 2 of 20 patients deceased from non-neurological causes and in 4 of 10 patients with other neurodegenerative diseases. Comparison was made with 17 patients with 9 different mutations. Morphologically, the inclusions in patients with mutations in and resembled inclusions in patients carrying the wildtype-like mutation, whereas patients carrying unstable mutations (A4V, V5M, D76Y, D83G, D101G, G114A, G127X, L144F) had larger skein-like SOD1-positive inclusions.

CONCLUSIONS AND RELEVANCE

Abundant inclusions containing misfolded SOD1 are found in spinal and cortical motor neurons in patients carrying mutations in six ALS-causing genes other than . This suggests that misfolding of SOD1 can be part of a common downstream event that may be pathogenic. The new anti-SOD1 therapeutics in development may have applications for a broader range of patients.