Misfolded SOD1 inclusions in patients with mutations in <i>C9orf72</i> and other ALS/FTD-associated genes.

Abstract

A hallmark of amyotrophic lateral sclerosis (ALS) caused by mutations in <i>superoxide dismutase-1</i> (<i>SOD1</i>) 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. A panel of antibodies that specifically recognise misfolded SOD1 species were used for immunohistochemical investigations of autopsy tissue. The 18 patients with hexanucleotide-repeat-expansions in <i>C9orf72</i> had inclusions of misfolded wild type (WT) SOD1^WT in spinal motor neurons. Similar inclusions were occasionally observed in medulla oblongata and in the motor cortex and frontal lobe. Patients with mutations in <i>FUS, KIF5A, NEK1, ALSIN</i> or <i>VAPB</i>, carried similar SOD1^WT inclusions. Minute amounts of misSOD1^WT 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 <i>SOD1</i> mutations. Morphologically, the inclusions in patients with mutations in <i>C9orf72HRE, FUS, KIF5A, NEK1, VAPB</i> and <i>ALSIN</i> resembled inclusions in patients carrying the wildtype-like <i>SOD1^D90A</i> mutation, whereas patients carrying unstable <i>SOD1</i> mutations (A4V, V5M, D76Y, D83G, D101G, G114A, G127X, L144F) had larger skein-like SOD1-positive inclusions. Abundant inclusions containing misfolded SOD1^WT are found in spinal and cortical motor neurons in patients carrying mutations in six ALS-causing genes other than <i>SOD1</i>. This suggests that misfolding of SOD1^WT 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.