Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease of the motor neurons, which leads to paralysis and death within 3-5 years from diagnosis. ALS is mainly sporadic (SALS) without a known cause. Only a small fraction of ALS is familial (FALS). Thus, one of the biggest challenges in the study of the disease is how to reconcile disease mechanisms among the small percentage of familial cases and the vast majority of sporadic cases with no known etiology. It is crucial that we identify common pathogenic mechanisms between the two forms of the disease. Mitochondrial pathology is one of these common pathways, as mitochondria defects have been found in both SALS patients and transgenic mutant SOD1 (mutSOD1) mice model of ALS. Whether similar triggers in FALS and SALS damage the mitochondria is not known. Using mutSOD1 expressing cells and transgenic mice (to mimic FALS), as well as EVB immortalized lymphoblasts from SALS patients, we identified a potentially common trigger mechanism. In mutSOD1 mice, we showed that mutSOD1 aberrantly binds and forms a toxic complex with Bcl-2 in mitochondria. Upon this aberrant binding, mutSOD1 induces a conformational change in Bcl-2 that transforms it into a harmful protein by exposing the normally hidden toxic BH3 domain. Together, mutSOD1 and conformationally modified Bcl-2 impair mitochondrial viability, eventually inducing cell death. Interestingly, in a subset (~ 30%) of SALS patients with upper motor neuron onset, an oxidized form of wild type SOD1 aberrantly binds to Bcl-2, transforming Bcl- 2 into a toxic molecule through exposure of the BH3 domain, similarly to what we have reported for mutSOD1. With this competing renewal, we intend to focus on this common pathway of mitochondrial dysfunction shared by FALS-SOD1 and a subset of SALS patients. We will test in vivo the hypothesis that the conformational change in Bcl-2 leading to exposure of the toxic BH3 domain is an important mechanism in SOD1-induced mitochondrial dysfunction (AIM 1). We will then characterize the functional implications of the toxic complex between SOD1 and Bcl-2 by identifying key downstream mitochondrial target(s) (AIM 2) and determining the cellular specificity of the SOD1/Bcl-2-mediated mitochondrial dysfunction (AIM 3). Finally, we will test the beneficial effect of SOD1-like peptides that inhibit binding to Bcl-2 against SOD1-mediated cell death (AIM 4). The ultimate goal is to identify target-based therapies whose efficacy goes beyond the limited portion of familial cases.

Public Health Relevance

In most patients with Amyotrophic Lateral Sclerosis [(ALS)-a lethal neurodegenerative disease that leads to paralysis and death 3-5 years from diagnosis], there is no family link and only a minority of cases (10%) has a genetic link. Because all forms of ALS (with or without a genetic link) are clinically similar, the assumption is that they are also similar in their pathogenesis and the goal for scientists is to identify common pathogenic pathways. Using ALS mouse models (with a genetic mutation) and cells derived from patients without a genetic link, we will study a potentially common mechanism of disease pathogenesis that targets the powerhouse of cells (mitochondria).

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Gubitz, Amelie
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Thomas Jefferson University
Schools of Medicine
United States
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