Alpha-synuclein impairs normal dynamics of mitochondria in cell and animal models of Parkinson's disease

Xie, Weilin

doi:10.14711/thesis-b1155461

Cited by 22 publications

(30 citation statements)

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“…146 A mutation in a-Syn (A53T) that causes familial PD has been shown to affect mitochondrial dynamics by reducing interconnectivity and increasing circularity of mitochondria in an age-dependent manner, thereby leading to neurodegeneration in an animal model of PD. 147 The above changes in mitochondria are also in part due to agedependent reduction in the levels of Mfn1 and Mfn2 in A53T a-Syn mice. 147 Moreover, a-Syn has been shown to promote translocation of Drp1 to mitochondria, and Drp1 is required for a-Syn-induced mitochondrial fragmentation.…”

Section: Mitochondrial Fragmentation and Neurodegenerative Diseasesmentioning

confidence: 97%

“…147 The above changes in mitochondria are also in part due to agedependent reduction in the levels of Mfn1 and Mfn2 in A53T a-Syn mice. 147 Moreover, a-Syn has been shown to promote translocation of Drp1 to mitochondria, and Drp1 is required for a-Syn-induced mitochondrial fragmentation. 145 Taken together, all the evidence suggests that mitochondrial fragmentation is a major contributor in initiation and progression of neurodegenerative diseases.…”

Section: Mitochondrial Fragmentation and Neurodegenerative Diseasesmentioning

confidence: 97%

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Mitochondrial fission and fusion in secondary brain damage after CNS insults

Balog

Mehta

Vemuganti

2016

J Cereb Blood Flow Metab

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Mitochondria are dynamically active organelles, regulated through fission and fusion events to continuously redistribute them across axons, dendrites, and synapses of neurons to meet bioenergetics requirements and to control various functions, including cell proliferation, calcium buffering, neurotransmission, oxidative stress, and apoptosis. However, following acute or chronic injury to CNS, altered expression and function of proteins that mediate fission and fusion lead to mitochondrial dynamic imbalance. Particularly, if the fission is abnormally increased through pro-fission mediators such as Drp1, mitochondrial function will be impaired and mitochondria will become susceptible to insertion of proapototic proteins. This leads to the formation of mitochondrial transition pore, which eventually triggers apoptosis. Thus, mitochondrial dysfunction is a major promoter of neuronal death and secondary brain damage after an insult. This review discusses the implications of mitochondrial dynamic imbalance in neuronal death after acute and chronic CNS insults.

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Section: Mitochondrial Fragmentation and Neurodegenerative Diseasesmentioning

confidence: 97%

Section: Mitochondrial Fragmentation and Neurodegenerative Diseasesmentioning

confidence: 97%

Mitochondrial fission and fusion in secondary brain damage after CNS insults

Balog

Mehta

Vemuganti

2016

J Cereb Blood Flow Metab

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“…Aggregation of the α-synuclein protein or mutations in the α-synuclein gene (A53T) which lead to an impairment of mitochondrial dynamics, morphology, and movement have been linked to rare inherited forms of PD (Polymeropoulos et al 1997;Spillantini et al 1997;Xie and Chung 2012). One study identified a 22 kDa O-glycosylated form of α-synuclein in a protein complex with parkin (an E3 ubiquitin ligase) and UbcH7 (an E2 ubiquitin-conjugating enzyme).…”

Section: Parkinson's Diseasementioning

confidence: 99%

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

Groves

Lee

Yildirir

et al. 2013

Cell Stress and Chaperones

120

112

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O-linked N-acetyl-β-D-glucosamine (O-GlcNAc) is a ubiquitous and dynamic post-translational modification known to modify over 3,000 nuclear, cytoplasmic, and mitochondrial eukaryotic proteins. Addition of O-GlcNAc to proteins is catalyzed by the O-GlcNAc transferase and is removed by a neutral-N-acetyl-β-glucosaminidase (OGlcNAcase). O-GlcNAc is thought to regulate proteins in a manner analogous to protein phosphorylation, and the cycling of this carbohydrate modification regulates many cellular functions such as the cellular stress response. Diverse forms of cellular stress and tissue injury result in enhanced O-GlcNAc modification, or O-GlcNAcylation, of numerous intracellular proteins. Stress-induced OGlcNAcylation appears to promote cell/tissue survival by regulating a multitude of biological processes including: the phosphoinositide 3-kinase/Akt pathway, heat shock protein expression, calcium homeostasis, levels of reactive oxygen species, ER stress, protein stability, mitochondrial dynamics, and inflammation. Here, we will discuss the regulation of these processes by O-GlcNAc and the impact of such regulation on survival in models of ischemia reperfusion injury and trauma hemorrhage. We will also discuss the misregulation of O-GlcNAc in diseases commonly associated with the stress response, namely Alzheimer's and Parkinson's diseases. Finally, we will highlight recent advancements in the tools and technologies used to study the O-GlcNAc modification.

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“…Membrane interaction has also been proposed to play a significant role in the pathogenesis of Parkinson disease, as ␣S can disrupt cellular membranes. Damage to mitochondria is a commonly found feature of ␣S expression (11)(12)(13)(14)(15), but disruption of other cellular membranes such as Golgi (16,17), lysosomes (18), endoplasmic reticulum, and nucleus (19) has also been reported.…”

Section: ␣-Synuclein (␣S)mentioning

confidence: 99%

α-Synuclein Oligomers with Broken Helical Conformation Form Lipoprotein Nanoparticles

Varkey

Mizuno

Hegde

et al. 2013

Journal of Biological Chemistry

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Background:Parkinson disease protein ␣-synuclein has sequence similarity with apolipoproteins. Results: ␣-Synuclein can generate nanoparticles from phospholipid membranes and fatty acids by taking up a broken helical structure. Conclusion: These nanoparticles have shapes and dimensions reminiscent of apolipoprotein nanodiscs. Significance: The data suggest apolipoprotein-like roles for ␣-synuclein as a lipid-or fatty acid-carrying protein.

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Alpha-synuclein impairs normal dynamics of mitochondria in cell and animal models of Parkinson's disease

Cited by 22 publications

References 0 publications

Mitochondrial fission and fusion in secondary brain damage after CNS insults

Mitochondrial fission and fusion in secondary brain damage after CNS insults

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

α-Synuclein Oligomers with Broken Helical Conformation Form Lipoprotein Nanoparticles

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