α-Synuclein Promotes Mitochondrial Deficit and Oxidative Stress

Hsu, Leigh J.; Sagara, Yutaka; Arroyo, Amanda; Rockenstein, Edward; Sisk, Abbyann; Mallory, Margaret; Wong, J.Y.C.; Takenouchi, Takato; Hashimoto, Makoto; Masliah, Eliezer

doi:10.1016/s0002-9440(10)64553-1

Cited by 652 publications

(455 citation statements)

References 53 publications

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“…Of these five genes, ␣-Syn, parkin, and DJ-1 have been most intensively studied. Studies using in vivo animal models and in vitro cell culture have linked mutations of these genes to impairments of mitochondrial structure and function and oxidative stress response, reinforcing the general involvement of mitochondrial dysfunction and oxidative stress in PD pathogenesis (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Consistent with this notion, these proteins have been shown to be present in mitochondria or interact with mitochondrial proteins (8,(22)(23)(24), suggesting that they may directly regulate mitochondria function.…”

mentioning

confidence: 79%

Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin

Yang

Gehrke²,

Imai³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

721

724

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Mutations in Pink1, a gene encoding a Ser͞Thr kinase with a mitochondrial-targeting signal, are associated with Parkinson's disease (PD), the most common movement disorder characterized by selective loss of dopaminergic neurons. The mechanism by which loss of Pink1 leads to neurodegeneration is not understood. Here we show that inhibition of Drosophila Pink1 (dPink1) function results in energy depletion, shortened lifespan, and degeneration of select indirect flight muscles and dopaminergic neurons. The muscle pathology was preceded by mitochondrial enlargement and disintegration. These phenotypes could be rescued by the wild type but not the pathogenic C-terminal deleted form of human Pink1 (hPink1). The muscle and dopaminergic phenotypes associated with dPink1 inactivation show similarity to that seen in parkin mutant flies and could be suppressed by the overexpression of Parkin but not DJ-1. Consistent with the genetic rescue results, we find that, in dPink1 RNA interference (RNAi) animals, the level of Parkin protein is significantly reduced. Together, these results implicate Pink1 and Parkin in a common pathway that regulates mitochondrial physiology and cell survival in Drosophila.mitochondria ͉ Parkinson's disease ͉ Pten-induced kinase 1 ͉ indirect flight muscle P arkinson's disease (PD) is the most common movement disorder characterized pathologically by the deficiency of brain dopamine content and the selective degeneration of dopaminergic neurons in the substantia nigra. The most common forms of PD are sporadic with no known cause. Nevertheless, postmortem studies have identified common features associated with sporadic PD, such as mitochondrial complex I dysfunction, oxidative stress, and aggregation of abnormal proteins (1, 2).Although initial studies on the etiology of PD have focused on environmental factors, recent genetic studies have firmly established the contribution of inheritable factors in PD pathogenesis (2, 3). At least ten distinct loci have been associated with rare familial forms of PD (FPD). It is anticipated that understanding the molecular lesions associated with these FPD genes will shed light on the pathogenesis of the more common forms of the disease. Dominant mutations in ␣-Synuclein (␣-Syn) and LRRK2͞dardarin and recessive mutations in parkin, DJ-1, and Pink1 have been associated with FPD (4-10). Of these five genes, ␣-Syn, parkin, and DJ-1 have been most intensively studied. Studies using in vivo animal models and in vitro cell culture have linked mutations of these genes to impairments of mitochondrial structure and function and oxidative stress response, reinforcing the general involvement of mitochondrial dysfunction and oxidative stress in PD pathogenesis (11-21). Consistent with this notion, these proteins have been shown to be present in mitochondria or interact with mitochondrial proteins (8,(22)(23)(24), suggesting that they may directly regulate mitochondria function.A further link between mitochondria and PD was supported by the fact that Pink1 encodes a predicted Se...

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mentioning

confidence: 79%

Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin

Yang

Gehrke²,

Imai³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

721

724

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“…Cells of the immortalized hypothalamic neuronal cell line GT1-7 (a gift from P. Mellon, University of California at San Diego) express neuronal markers, form synapses, produce neurotransmitters (26) and, on transfection with SYN, show mitochondrial alterations, inclusion body formation, evidence of oxidative stress, and synaptic dysfunction (27). Cells were stably transfected with SYN cDNA or control plasmid as described (27), plated in 24-well plates coated with poly-L-lysine (5 ϫ 10 4 ͞0.5 ml of DMEM with 10% serum and without G418), and treated with synthetic peptides from Sigma as outlined in Fig. 6.…”

Section: Methodsmentioning

confidence: 99%

“…6. For quantitation of SYN-immunoreactive inclusions, coverslips were immunostained (27) (28), anti-choline acetyltransferase (ChAT; AB143, 1:1000, Chemicon), and anti-synaptophysin (SY38, 1:10, Chemicon). The specificity of immunostaining results was confirmed by incubating sections or cells overnight with preimmune serum or without primary antibody.…”

Section: Methodsmentioning

confidence: 99%

“…The membrane was then incubated with 125 I-labeled protein A (ICN), followed by autoradiography. (e-j) Neuronal GT1-7 cells stably transfected with SYN cDNA (e-g) or control plasmid (h-j) as described (27), were left untreated (e and h) or exposed for 48 h to A␤1-40 ( f and i), A␤1-42 (g and j), or A␤42-1 (not shown) at 2 M final concentration, followed by immunoperoxidase staining with anti-SYN (27). (47)(48)(49).…”

Section: A␤ Promotes Accumulation Of Hsynmentioning

confidence: 99%

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β-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease

Masliah

Rockenstein

Veinbergs

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

567

466

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Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of ␤-amyloid and ␣-synuclein, respectively. Some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenetic pathways. We generated transgenic (tg) mice with neuronal expression of human ␤-amyloid peptides, ␣-synuclein, or both. The functional and morphological alterations in doubly tg mice resembled the Lewy-body variant of Alzheimer's disease. These mice had severe deficits in learning and memory, developed motor deficits before ␣-synuclein singly tg mice, and showed prominent agedependent degeneration of cholinergic neurons and presynaptic terminals. They also had more ␣-synuclein-immunoreactive neuronal inclusions than ␣-synuclein singly tg mice. Ultrastructurally, some of these inclusions were fibrillar in doubly tg mice, whereas all inclusions were amorphous in ␣-synuclein singly tg mice. ␤-Amyloid peptides promoted aggregation of ␣-synuclein in a cell-free system and intraneuronal accumulation of ␣-synuclein in cell culture. ␤-Amyloid peptides may contribute to the development of Lewy-body diseases by promoting the aggregation of ␣-synuclein and exacerbating ␣-synuclein-dependent neuronal pathologies. Therefore, treatments that block the production or accumulation of ␤-amyloid peptides could benefit a broader spectrum of disorders than previously anticipated.A ging is a major risk factor for neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD), and the number of people with these conditions is increasing rapidly. In the United States alone, an estimated 4 million people have AD and at least one million have PD. Within the next 40-50 years, these numbers are projected to increase to over 8 million for AD and to 4 million for PD. Each neurodegenerative disease appears to have a predilection for specific brain regions and cell populations. However, human cases with clinical and neuropathological features of both AD and PD (1-3) raise the possibility that these diseases involve overlapping pathways.Many AD patients develop signs of PD and some PD patients become demented (3). Both diseases are associated with degeneration of neurons and interneuronal synaptic connections, depletion of specific neurotransmitters, and abnormal accumulation of misfolded proteins, whose precursors participate in normal central nervous system functions (4-11). The ␤-amyloid protein precursor (APP) and ␣-synuclein (SYN) are expressed abundantly in synapses, are well conserved across species, and have been implicated in neural plasticity, learning, and memory (6,7,12). Mutations in human APP (hAPP) that increase production of hAPP-derived ␤-amyloid peptides (A␤) cause autosomal dominant forms of familial AD (FAD) (11), and expression of FAD-mutant hAPPs in neurons of transgenic (tg) mice results in the age-dependent development of AD-like central nervous system alterations (13-17). Mutations in human SYN (hSYN) that enhance hSYN aggregation have bee...

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“…␣Syn may associate abnormally with mitochondria in PD patients and animal models (27)(28)(29)(30)(31)(32)(33). An apparent partial subcellular redistribution of ␣Syn from the cytoplasm to the inner and outer mitochondrial membranes (27,34,35) is correlated with mitochondrial dysfunction, including increased oxidative stress, reduced mitochondrial membrane potential (⌬⌿ m ), altered Ca 2ϩ homeostasis, and cytochrome c release (27, 29 -31, 33, 36, 37).…”

mentioning

confidence: 99%

Soluble, Prefibrillar α-Synuclein Oligomers Promote Complex I-dependent, Ca2+-induced Mitochondrial Dysfunction

Luth

Stavrovskaya

Bartels

et al. 2014

Journal of Biological Chemistry

250

181

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α-Synuclein Promotes Mitochondrial Deficit and Oxidative Stress

Cited by 652 publications

References 53 publications

Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin

Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin

β-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease

Soluble, Prefibrillar α-Synuclein Oligomers Promote Complex I-dependent, Ca2+-induced Mitochondrial Dysfunction

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