Neurons are highly dependent on mitochondrial metabolism, because of high energetic demands and the need to maintain intracellular calcium homeostasis. To provide energy to the extensive neuronal cytoplasm of large projections cells, such as motor neurons, the mitochondrial network has to be adequately maintained and distributed. Dynamic mitochondrial transport, fusion, and fission, ensure that healthy mitochondria are provided at sites of high-energy utilization and calcium buffering. New mitochondria are generated by regulated biogenesis and damaged mitochondria are subjected to quality control (MQC): damaged proteins are removed by proteolytic and proteosomal systems. Irreparably damaged mitochondria are eliminated by mitophagy. The balance between mitochondrial biogenesis and mitochondrial elimination ensures that adequate pools of functional mitochondria are available and that accumulated damaged mitochondria do not release toxic molecules, such as free radicals and pro-apoptotic factors, or excessive amounts of calcium. Extensive mitochondrial damage in motor neurons has been described in vitro and in vivo in mutant SOD1 models and in other forms of familial and sporadic ALS, raising two fundamental questions: 1) Why in SOD1- ALS MQC is incapable of clearing damaged mitochondria? We found an increase in the ubiquitin-binding adaptor p62 associated with mitochondria, suggesting enhanced mitophagy, but delayed mitochondrial clearance. We also found that Parkin, an ubiquitin ligase involved in both proteosomal degradation of mitochondrial proteins and mitophagy, is decreased. 2) Does the failure to clear of damaged mitochondria play a role in the pathogenesis of SOD1-ALS? This question implies that impaired MCQ may lead to accumulation of damaged mitochondria and play a pathogenic role. The overarching hypothesis of this application is that in ALS motor neurons MQC fails, either because the demand exceeds capabilities or because the MQC is dysfunctional. To test this hypothesis and study the underlying mechanisms we propose two specific aims, each with two sets of studies.
Specific Aim 1 will investigate the causes of MQC impairment in SOD1-ALS. Study 1 will identify which steps of the MQC are impaired in mutant SOD1 neurons in vivo and in vitro. Study 2 will determine if MQC impairment in SOD1 motor neurons is caused by excessive mitochondrial damage.
Specific Aim 2 will assess the effects of Parkin modulation in SOD1-ALS. Study 1 will assess the impact of inducible/conditional genetic deletion of the MQC component Parkin on SOD1-ALS. Study 2 will assess the impact of Parkin genetic overexpression on SOD1-ALS. The application aims at the mechanistic understanding of a pathogenic pathway that links MQC with mitochondrial dysfunction and motor neuron degeneration in SOD1-ALS. The findings will unveil novel disease mechanisms that could be addressed therapeutically by targeted approaches aimed at modulating mitochondria MQC in ALS and other neurodegenerative diseases by pharmacological intervention.

Public Health Relevance

Mitochondria play an essential role in neurons and mitochondrial abnormalities are common denominators of many types of neurodegenerative diseases. In familial ALS caused by mutations in SOD1, motor neurons accumulate abnormal and dysfunctional mitochondria. The mechanisms of mitochondria quality control (MQC) that eliminate damaged mitochondria fail, suggesting that MQC in ALS motor neurons is ineffective. As a consequence, damaged mitochondria can become toxic. This application will investigate the MQC failure in SOD1 mutant neurons and its contribution ALS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Gubitz, Amelie
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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Palomo, Gloria M; Granatiero, Veronica; Kawamata, Hibiki et al. (2018) Parkin is a disease modifier in the mutant SOD1 mouse model of ALS. EMBO Mol Med 10:
Riar, Amanjot K; Burstein, Suzanne R; Palomo, Gloria M et al. (2017) Sex specific activation of the ER? axis of the mitochondrial UPR (UPRmt) in the G93A-SOD1 mouse model of familial ALS. Hum Mol Genet 26:1318-1327
Kawamata, Hibiki; Peixoto, Pablo; Konrad, Csaba et al. (2017) Mutant TDP-43 does not impair mitochondrial bioenergetics in vitro and in vivo. Mol Neurodegener 12:37
Konrad, Csaba; Kawamata, Hibiki; Bredvik, Kirsten G et al. (2017) Fibroblast bioenergetics to classify amyotrophic lateral sclerosis patients. Mol Neurodegener 12:76
Kawamata, Hibiki; Manfredi, Giovanni (2017) Proteinopathies and OXPHOS dysfunction in neurodegenerative diseases. J Cell Biol 216:3917-3929
Manfredi, Giovanni; Kawamata, Hibiki (2016) Mitochondria and endoplasmic reticulum crosstalk in amyotrophic lateral sclerosis. Neurobiol Dis 90:35-42
Palomo, Gloria M; Manfredi, Giovanni (2015) Exploring new pathways of neurodegeneration in ALS: the role of mitochondria quality control. Brain Res 1607:36-46
Ikiz, Burcin; Alvarez, Mariano J; Ré, Diane B et al. (2015) The Regulatory Machinery of Neurodegeneration in In Vitro Models of Amyotrophic Lateral Sclerosis. Cell Rep 12:335-45
Magrané, Jordi; Cortez, Czrina; Gan, Wen-Biao et al. (2014) Abnormal mitochondrial transport and morphology are common pathological denominators in SOD1 and TDP43 ALS mouse models. Hum Mol Genet 23:1413-24
Papa, Luena; Manfredi, Giovanni; Germain, Doris (2014) SOD1, an unexpected novel target for cancer therapy. Genes Cancer 5:15-21

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