Current Search: amyotrophic lateral sclerosis (x)
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- Title
- Defective Dynamics of Mitochondria in Amyotrophic Lateral Sclerosis and Huntington's Disease.
- Creator
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Song, Wenjun, Bossy-Wetzel, Ella, Fernandez-Valle, Cristina, Cheng, Zixi, Self, William, University of Central Florida
- Abstract / Description
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Mitochondria play important roles in neuronal function and survival, including ATP production, Ca2+ buffering, and apoptosis. Mitochondrial dysfunction is a common event in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD); however, what causes the mitochondrial dysfunction remains unclear. Mitochondrial fission is mediated by dynamin-related protein 1 (DRP1) and fusion by mitofusin 1/2 (MFN1/2) and optic atrophy 1 (OPA1),...
Show moreMitochondria play important roles in neuronal function and survival, including ATP production, Ca2+ buffering, and apoptosis. Mitochondrial dysfunction is a common event in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD); however, what causes the mitochondrial dysfunction remains unclear. Mitochondrial fission is mediated by dynamin-related protein 1 (DRP1) and fusion by mitofusin 1/2 (MFN1/2) and optic atrophy 1 (OPA1), which are essential for mitochondrial function. Mutations in the mitochondrial fission and fusion machinery lead to neurodegeneration. Thus, whether defective mitochondrial dynamics participates in ALS and HD requires further investigation.ALS is a fatal neurodegenerative disease characterized by upper and lower motor neuron loss. Mutations in Cu/Zn superoxide dismutase (SOD1) cause the most common familiar form of ALS by mechanisms not fully understood. Here, a new motor neuron-astrocyte co-culture system was created and live-cell imaging was used to evaluate mitochondrial dynamics. Excessive mitochondrial fission was observed in mutant SOD1G93A motor neurons, correlating with impaired axonal transport and neuronal cell death. Inhibition of mitochondrial fission restored mitochondrial dynamics and protected neurons against SOD1G93A-induced mitochondrial fragmentation and neuronal cell death, implicating defects in mitochondrial dynamics in ALS pathogenesis.HD is an inherited neurodegenerative disorder caused by glutamine (Q) expansion in the polyQ region of the huntingtin (HTT) protein. In the current work, mutant HTT caused mitochondrial fragmentation in a polyQ-dependent manner in both primary cortical neurons and fibroblasts from human patients. An abnormal interaction between DRP1 and HTT was observed in mutant HTT mice and inhibition of mitochondrial fission or promotion of mitochondrial fusion restored mitochondrial dynamics and protected neurons against mutant HTT-induced cell death. Thus, mutant HTT may increase mitochondrial fission by elevating DRP1 GTPase activity, suggesting that mitochondrial dynamics plays a causal role in HD.In summary, rebalanced mitochondrial fission and fusion rescues neuronal cell death in ALS and HD, suggesting that mitochondrial dynamics could be the molecular mechanism underlying these diseases. Furthermore, DRP1 might be a therapeutic target to delay or prevent neurodegeneration.
Show less - Date Issued
- 2012
- Identifier
- CFE0004444, ucf:49356
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0004444
- Title
- The Role of SOD1 Acetylation in Neurodegeneration.
- Creator
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Kaliszewski, Michael, Bossy-Wetzel, Ella, Estevez, Alvaro, Kim, Yoon-Seong, Tatulian, Suren, University of Central Florida
- Abstract / Description
-
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting motor neurons. Cu, Zn superoxide dismutase (SOD1), a cytoplasmic free radical scavenging enzyme, is mutated in familial ALS (fALS) and post-translational modification of the wild-type protein has been associated with sporadic ALS (sALS). Proteomic studies indicate that SOD1 is acetylated at Lys123; however, the role of this modification remains unknown. To investigate its function, we generated antibodies for...
Show moreAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting motor neurons. Cu, Zn superoxide dismutase (SOD1), a cytoplasmic free radical scavenging enzyme, is mutated in familial ALS (fALS) and post-translational modification of the wild-type protein has been associated with sporadic ALS (sALS). Proteomic studies indicate that SOD1 is acetylated at Lys123; however, the role of this modification remains unknown. To investigate its function, we generated antibodies for Lys123-acetylated SOD1 (Ac-K123 SOD1). Sod1 deletion in Sod1-/- mice, K123 mutation, or preabsorption with Ac-K123 peptide suppressed immunoreactivity, confirming antibody specificity. In the normal central nervous system, Ac-K123 SOD1 maps to glutamatergic neurons of the cerebellar cortex, dentate gyrus, hippocampus, olfactory bulb, and retina. In cultured neurons, Ac-K123 SOD1 localized to defined regions of axons and dendrites. Previous studies have suggested a role for SOD1 in cell cycle regulation. Therefore, we tested the distribution of Ac-K123 SOD1 during the cell cycle of astrocytes. In G1 Ac-K123 SOD1 localized to the nucleus, in G0 to the primary cilium, in metaphase and anaphase to chromosomes, and in telophase to the midbody. The deacetylase HDAC6 and acetyl-transferase ?-TAT1 are associated with the primary cilium. Therefore, we tested whether they regulate reversible acetylation of SOD1. HDAC6 knockdown or pharmacological inhibition markedly increased, while HDAC6 overexpression decreased, SOD1 Lys123 acetylation. By contrast, SOD1 Lys123 acetylation was decreased by ?-TAT1 knockdown and increased by ?-TAT1 overexpression. These results suggest that HDAC6 and ?-TAT1 regulate SOD1 Lys123 acetylation. Next, we examined Lys123 acetylation in fALS SOD1 mutants. Remarkably, Lys123 acetylation was dramatically increased in fALS mutants including SOD1 A4V. The acetyl-Lys123 mimetic of wild-type SOD1 caused axonal transport deficits similar to those observed in SOD1 pathogenic mutants such as A4V. Interestingly, HDAC6 deacetylation or acetylation resistance by Lys123 mutation, abolished A4V protein misfolding, axonal transport defects, and neuronal cell death. These results suggest that Lys123 acetylation plays a key role in the neurotoxicity of fALS mutants and may have implications in sALS. Because Ac-K123 SOD1 maps to the primary cilium, we examined whether ciliogenesis is altered in fALS mutant SOD1 astrocytes. Strikingly, fALS mutants caused centriole and primary cilia proliferation with ciliary ectosome secretion. Notably, multiciliated ependymal cells in the brain ventricles and spinal cord central canal, which are critical for cerebral spinal fluid circulation, stained strongly for Ac-K123 SOD1. Thus, we speculate that ciliary ectosome shedding from ependymal cells accounts for the presence of misfolded SOD1 in the CSF in fALS and perhaps sALS. In summary, we identified SOD1 Lys123 acetylation as a novel mechanism underlying protein misfolding and neurodegeneration in ALS. Ac-K123 SOD1 may emerge as novel target for the diagnosis and treatment of ALS.
Show less - Date Issued
- 2016
- Identifier
- CFE0006467, ucf:51409
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0006467