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).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS051488-08
Application #
8411141
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Gubitz, Amelie
Project Start
2006-08-02
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
8
Fiscal Year
2013
Total Cost
$331,399
Indirect Cost
$117,593
Name
Thomas Jefferson University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Kia, Azadeh; McAvoy, Kevin; Krishnamurthy, Karthik et al. (2018) Astrocytes expressing ALS-linked mutant FUS induce motor neuron death through release of tumor necrosis factor-alpha. Glia 66:1016-1033
Jablonski, Michael; Miller, David S; Pasinelli, Piera et al. (2015) ABC transporter-driven pharmacoresistance in Amyotrophic Lateral Sclerosis. Brain Res 1607:1-14
Wen, Xinmei; Tan, Wenzhi; Westergard, Thomas et al. (2014) Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron 84:1213-25
Tan, Wenzhi; Pasinelli, Piera; Trotti, Davide (2014) Role of mitochondria in mutant SOD1 linked amyotrophic lateral sclerosis. Biochim Biophys Acta 1842:1295-301
Tan, Wenzhi; Naniche, Nicole; Bogush, Alexey et al. (2013) Small peptides against the mutant SOD1/Bcl-2 toxic mitochondrial complex restore mitochondrial function and cell viability in mutant SOD1-mediated ALS. J Neurosci 33:11588-98
Bowling, C Barrett; Booth 3rd, John N; Safford, Monika M et al. (2013) Nondisease-specific problems and all-cause mortality in the REasons for Geographic and Racial Differences in Stroke study. J Am Geriatr Soc 61:739-46
Jablonski, Michael R; Jacob, Dena A; Campos, Christopher et al. (2012) Selective increase of two ABC drug efflux transporters at the blood-spinal cord barrier suggests induced pharmacoresistance in ALS. Neurobiol Dis 47:194-200
Guareschi, Stefania; Cova, Emanuela; Cereda, Cristina et al. (2012) An over-oxidized form of superoxide dismutase found in sporadic amyotrophic lateral sclerosis with bulbar onset shares a toxic mechanism with mutant SOD1. Proc Natl Acad Sci U S A 109:5074-9
Naniche, Nicole; Sau, Daniela; Pasinelli, Piera (2011) In vivo and in vitro determination of cell death markers in neurons. Methods Mol Biol 793:9-21
Foran, Emily; Bogush, Alexey; Goffredo, Michael et al. (2011) Motor neuron impairment mediated by a sumoylated fragment of the glial glutamate transporter EAAT2. Glia 59:1719-31

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