Studies of mitochondrial dysfunction in mutant SOD1-mediated ALS and therapeutic implications

Nicole Guarino, Thomas Jefferson University

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative, fatal disease affecting mainly motor neurons in the motor cortex, brainstem and spinal cord. Approximately 2% of all ALS cases are caused by mutations in superoxide dismutase 1 (SOD1). Although motor neurons predominately die in ALS, we know that other non-neuronal cells actively contribute to disease. The underlying cause of motor neuron death is unknown; however, alterations to mitochondrial morphology and function are seen preceding onset in a mouse model of ALS. This suggests that damage to mitochondria is a key pathogenic feature. Mutated SOD1 (mutSOD1) has been shown to bind aberrantly to mitochondrial proteins; notably, with Bcl-2, a normally protective protein found in the outer mitochondrial membrane that also plays an important role in regulation of mitochondrial homeostasis. Based on the findings that mutSOD1 targets mitochondrial Bcl-2 in brain and spinal cord, we hypothesize that (1) mutSOD1 requires Bcl-2 to damage mitochondria, and (2) the effect on Bcl-2 is not motor neuron specific. The studies of this thesis aimed to test these hypotheses. By using cells that lack detectable levels of Bcl-2, we were able to determine that both mitochondrial localization and toxicity of mutSOD1 are dependent on Bcl-2. This toxicity is mediated by a conformational change in Bcl-2 that exposes the normally hidden toxic BH3 domain, becoming a toxic protein that destroys mitochondrial morphology and integrity. Downstream of mutSOD1/Bcl-2 the major affected mitochondrial protein is VDAC1. We found that conformationally changed Bcl-2 also alters its binding to VDAC1. The binding between BH3-exposed Bcl-2 and VDAC1 increases over disease progression in ALS mice, and mitochondria show decreased ADP consumption. In an effort to block the the toxic mutSOD1/Bcl-2 binding, we created small SOD1-like peptides and identified one which we named P2. P2 was successfully able to not only block the binding, but also improve mitochondrial function. These studies were also able to begin to identify mechanisms of mutSOD1-induced mitochondrial dysfunction in glial cells. In conclusion, our studies identified a mechanism by which mutSOD1 damages mitochondria in ALS, and provided the bases for the development of a target-based therapy against mutSOD1-mediated mitochondrial damage.

Subject Area

Neurosciences

Recommended Citation

Guarino, Nicole, "Studies of mitochondrial dysfunction in mutant SOD1-mediated ALS and therapeutic implications" (2013). ETD Collection for Thomas Jefferson University. AAI3553084.
https://jdc.jefferson.edu/dissertations/AAI3553084

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