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SOD1 misplacing and mitochondrial dysfunction in amyotrophic lateral sclerosis pathogenesis

Francesco Tafuri¹, Dario Ronchi¹, Francesca Magri¹

¹Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico Milan, Italy.

Frontiers in Cellular Neuroscience

|September 18, 2015

Abstract:

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease presenting as sporadic (sALS) or familial (fALS) forms. Even if the list of the genes underlining ALS greatly expanded, defects in superoxide dismutase 1 (SOD1), encoding the copper/zinc SOD1, still remain a major cause of fALS and are likely involved also in apparently sporadic presentations. The pathogenesis of ALS is still unknown, but several lines of evidence indicate that the mitochondrial accumulation of mutant SOD1 is an important mechanism of mitochondrial dysfunction, leading to motor neuron pathology and death. The intramitochondrial localization of mutant SOD1 is debated. Mutant SOD1 might accumulate inside the intermembrane space (IMS), overriding the physiological retention regulated by the copper chaperone for superoxide dismutase (CCS). On the other hand, misfolded SOD1 might deposit onto the outer mitochondrial membrane (OMM), clumping the transport across mitochondrial membranes and engaging mitochondrial-dependent cell apoptosis. The elucidation of the mechanisms ruling SOD1 localization and misplacing might shed light on peculiar ALS features such as cell selectivity and late onset. More importantly, these studies might disclose novel targets for therapeutic intervention in familial ALS as well as non-genetic forms. Finally, pharmacological or genetic manipulation aimed to prevent or counteract the intracellular shifting of mutant SOD1 could be effective for other neurodegenerative disorders featuring the toxic accumulation of misfolded proteins.

Insights

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease linked to mutations in superoxide dismutase 1 (SOD1). Understanding how mutant SOD1 accumulates in mitochondria is key to developing new ALS therapies.

Area of Science:

Neuroscience
Molecular Biology
Genetics

Background:

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with sporadic (sALS) and familial (fALS) forms.
Mutations in superoxide dismutase 1 (SOD1) are a significant cause of fALS and may contribute to sALS.
Mitochondrial dysfunction due to mutant SOD1 accumulation is implicated in motor neuron pathology.

Purpose of the Study:

To investigate the intramitochondrial localization of mutant SOD1 in ALS pathogenesis.
To explore the mechanisms of mutant SOD1 mislocalization and its impact on mitochondrial function.
To identify potential therapeutic targets for ALS based on SOD1's cellular behavior.

Main Methods:

Review of existing evidence on SOD1 localization within mitochondria.
Analysis of the role of the copper chaperone for superoxide dismutase (CCS).
Discussion of potential consequences of SOD1 misplacement on the outer mitochondrial membrane (OMM).

Main Results:

Mutant SOD1 may accumulate in the mitochondrial intermembrane space (IMS), bypassing CCS regulation.
Alternatively, misfolded SOD1 might aggregate on the OMM, disrupting mitochondrial transport and triggering apoptosis.
The precise localization of mutant SOD1 influences disease mechanisms.

Conclusions:

Elucidating SOD1 localization mechanisms can explain ALS-specific features like cell selectivity and late onset.
Understanding SOD1's role may reveal novel therapeutic targets for both familial and sporadic ALS.
Strategies to prevent mutant SOD1 shifting could benefit other neurodegenerative diseases with misfolded protein accumulation.

Read full analysis

Keywords:

mitochondria mitochondrial intermembrane space motor neuron disorder outer mitochondrial membrane protein misfolding superoxide dismutase 1

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