This shows that SOD1 protein

‘Aberrant’ protein may be common link between all forms of motor neuron disease

To summarize: Abnormal SOD1 protein is a common factor in all types of motor neuron disease, a new study reports.

resource: University of Sydney

The researchers found that an abnormal protein commonly associated with rare inherited forms of motor neuron disease is present in all types of motor neuron disease, suggesting a common link between the different forms of the disease.

The study was published in the journal Neuroscience brainis the first to identify toxic changes in proteins in individuals with genetic or non-genetic forms of motor neuron disease.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. 10% of ALS cases are hereditary, and the remainder lack an obvious genetic cause.

“The results suggest that this abnormal protein causes cell death in many forms of motor neuron disease, not just rare genetic cases of motor neuron disease,” said senior author Kay of the Center for Brain and Mind in the School of Medicine and Health. Professor Double said.

“This is a huge step forward in advancing our understanding of motor neuron disease. Our findings will guide further research and may ultimately lead to more effective treatments.”

Normally, the protein superoxide dismutase 1 (SOD1) protects cells, but mutations in its gene are thought to make the protein “toxic”; this toxic form of the protein is associated with inherited forms of ALS. The abnormally mutated SOD1 was found only in regions of the spinal cord where nerve cells died, suggesting that this abnormal protein is involved in cell death.

Aberrant SOD1 protein was detected in human spinal cord tissue (black dots).Credit: Triest et al

Previous studies on the role of toxic forms of the SOD1 protein have focused on mutant forms of the protein, primarily using animal and cellular models of ALS.

The research, led by a team at the University of Sydney’s Centre for Brain and Mind, has advanced our understanding of the causes of motor neuron disease by studying this abnormal protein in postmortem tissue from ALS patients.

“We demonstrate for the first time that a disease mechanism long assumed to occur in animal and cellular models is present in patients with motor neuron disease,” said lead author Benjamin Trist, PhD, of the Center for Brain and Mind in the School of Medicine and Health.

“This is an important milestone in our broader understanding of ALS and motor neuron disease.”

In related experiments, Professor Double and her team are also currently studying how abnormal SOD1 interacts with other disease-related proteins in motor neuron disease.This work is in print and will be published in Neuropathology Communications.

Research news about this motor neuron disease

author: News office
resource: University of Sydney
touch: Press Office – University of Sydney
picture: This image is credited to Trist et al.

Original research: Open access.
“Altered SOD1 maturation and post-translational modifications in the spinal cord of amyotrophic lateral sclerosis”, Benjamin G Trist et al. brain

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Altered SOD1 maturation and post-translational modifications in the spinal cord of amyotrophic lateral sclerosis

Aberrant self-assembly and toxicity of wild-type and mutant superoxide dismutase 1 (SOD1) have been extensively studied computer, in vitro, and a transgenic animal model of amyotrophic lateral sclerosis (ALS). However, detailed examination of proteins in diseased tissue from ALS patients remains scarce.

We employed histological, biochemical, and analytical techniques to analyze changes in SOD1 protein deposition, subcellular localization, maturation, and post-translational modifications in postmortem spinal cord tissue from ALS cases and controls. Tissues were dissected into ventral and dorsal spinal cord gray matter to assess the specificity of alterations within areas of motor neuron degeneration.

We provide evidence for structurally disordered, mislocalized and accumulation of immature SOD1 protein conformers in spinal motor neurons. SOD1-Associative and non-SOD1Associated familial and sporadic ALS cases compared with control motor neurons. These changes are associated with the instability and mismetallation of the enzymatically active SOD1 dimer, as well as changes in SOD1 post-translational modifications and the molecular chaperones that control SOD1 maturation.

Atypical changes in SOD1 protein were largely confined to areas of neurodegeneration in ALS cases and clearly differentiated all forms of ALS from controls. Significant heterogeneity in these changes was also observed between ALS cases.

Our data suggest that different forms of SOD1 proteinopathy are a common feature of all forms of ALS and support the existence of one or more convergent biochemical pathways that lead to SOD1 proteinopathy in ALS. Most of these alterations are specific to areas of neurodegeneration and thus may constitute valid targets for therapeutic development.

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