Alpha‐synuclein protects cerebellar granule neurons against 6‐hydroxydopamine‐induced death

Monti, Barbara; Polazzi, Elisabetta; Batti, Laura; Crochemore, Christophe; Virgili, Marco; Contestabile, Antonio

doi:10.1111/j.1471-4159.2007.04778.x

Cited by 53 publications

(49 citation statements)

References 83 publications

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“…As previously demonstrated [22,30], exposure of differentiated rat CGNs to the dopaminergic toxin 6-OHDA (20 µ M ) resulted in approximately 50% cell death after -24 h (fig. 1a).…”

Section: Resultssupporting

confidence: 50%

Copper-Zinc Superoxide Dismutase (SOD1) Is Released by Microglial Cells and Confers Neuroprotection against 6-OHDA Neurotoxicity

Polazzi¹,

Mengoni²,

Caprini

et al. 2012

Neurosignals

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7,257

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Microglial-neuronal interactions are essential for brain physiopathology. In this framework, recent data have changed the concept of microglia from essentially macrophagic cells to crucial elements in maintaining neuronal homeostasis and function through the release of neuroprotective molecules. Using proteomic analysis, here we identify copper-zinc superoxide dismutase (SOD1) as a protein produced and released by cultured rat primary microglia. Evidence for a neuroprotective role of microglia-derived SOD1 resulted from experiments in which primary cerebellar granule neurons (CGNs) were exposed to the dopaminergic toxin 6-hydroxydopamine (6-OHDA). Microglial conditioned medium, in which SOD1 had accumulated, protected CGNs from degeneration, and neuroprotection was abrogated by SOD1 inhibitors. These effects were replicated when exogenous SOD1 was added to a nonconditioned medium. SOD1 neuroprotective action was mediated by increased cell calcium from an external source. Further experiments demonstrated the specificity of SOD1 neuroprotection against 6-OHDA compared to other types of neurotoxic challenges. SOD1, constitutively produced and released by microglia through a lysosomal secretory pathway, is identified here for the first time as an essential component of neuroprotection mediated by microglia. This novel information is relevant to stimulating further studies of microglia-mediated neuroprotection in in vivo models of neurodegenerative diseases.

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“…As previously demonstrated [22,30], exposure of differentiated rat CGNs to the dopaminergic toxin 6-OHDA (20 µ M ) resulted in approximately 50% cell death after -24 h (fig. 1a).…”

Section: Resultssupporting

confidence: 50%

Copper-Zinc Superoxide Dismutase (SOD1) Is Released by Microglial Cells and Confers Neuroprotection against 6-OHDA Neurotoxicity

Polazzi¹,

Mengoni²,

Caprini

et al. 2012

Neurosignals

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7,257

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show abstract

“…A recent communication (58) states, based on antisense oligonucleotide Syn silencing, that the protein has an essential pro-survival role toward primary neurons. Previous work has demonstrated that wild-type but not mutated Syn delayed death of neuronal cells after serum withdrawal (59), and protected cells by preventing activation of cell death-inducing proteins (caspases, p53, and Bad) (57,60).…”

Section: Discussionmentioning

confidence: 99%

Peroxidase Mechanism of Lipid-dependent Cross-linking of Synuclein with Cytochrome c

Bayır

Kapralov

Jiang

et al. 2009

Journal of Biological Chemistry

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Damage of presynaptic mitochondria could result in release of proapoptotic factors that threaten the integrity of the entire neuron. We discovered that ␣-synuclein (Syn) forms a triple complex with anionic lipids (such as cardiolipin) and cytochrome c, which exerts a peroxidase activity. The latter catalyzes covalent hetero-oligomerization of Syn with cytochrome c into high molecular weight aggregates. Syn is a preferred substrate of this reaction and is oxidized more readily than cardiolipin, dopamine, and other phenolic substrates. Lewy bodies (LBs), 3 mitochondrial impairment, and oxidative stress are cardinal features of Parkinson disease (PD) and several related neurodegenerative disorders (1, 2). Aggregation of ␣-synuclein (Syn), an abundant protein in synaptic terminals, plays a major role in the formation of LBs (3, 4). Neither the mechanisms of LB production nor their pathogenic or protective roles in neurodegeneration are well understood.In nigrostriatal dopaminergic synaptic terminals, mitochondria, harboring a host of death-initiating factors, are in peril of damage by reactive oxygen species generated by disrupted electron transport and/or oxidative metabolism of dopamine (DA). Because cytochrome c (cyt c)-dependent formation of apoptosomes and activation of caspases designates a point of no return in the apoptotic program, release of proapoptotic factors from synaptic mitochondria could threaten the integrity of the entire neuron. How neurons protect themselves against inadvertent release of death signals from damaged synaptic mitochondria is not known.The N-terminal fragment of Syn contains six variants of an 11-amino acid consensus motif that include an apolipoprotein-like class A2 helix participating in binding of different lipids, particularly anionic phospholipids (5). This domain is believed to be important for Syn functions in regulation of neuronal lipid metabolism, particularly turnover of a mitochondria-specific phospholipid, cardiolipin (CL) (6). However, the relevance of the Syn lipid binding capacity in regulating neuronal injury (apoptotic) responses has not been established.

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“…We have demonstrated here the potent impact of peptide delivery on PMO SSO therapy. In addition to SMA, other diseases for antisense oligonucleotide therapies include ALS (56, 57), Huntington's disease (58,59), and Parkinson's disease (60,61), which all ideally require both systemic and CNS SSO delivery. Future work will focus on extending further the clinical applications of Pip-PMOs.…”

Section: Discussionmentioning

confidence: 99%

Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy

Hammond

Hazell

Shabanpoor

et al. 2016

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

167

129

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The development of antisense oligonucleotide therapy is an important advance in the identification of corrective therapy for neuromuscular diseases, such as spinal muscular atrophy (SMA). Because of difficulties of delivering single-stranded oligonucleotides to the CNS, current approaches have been restricted to using invasive intrathecal single-stranded oligonucleotide delivery. Here, we report an advanced peptide-oligonucleotide, Pip6a-morpholino phosphorodiamidate oligomer (PMO), which demonstrates potent efficacy in both the CNS and peripheral tissues in severe SMA mice following systemic administration. SMA results from reduced levels of the ubiquitously expressed survival motor neuron (SMN) protein because of loss-of-function mutations in the SMN1 gene. Therapeutic splice-switching oligonucleotides (SSOs) modulate exon 7 splicing of the nearly identical SMN2 gene to generate functional SMN protein. Pip6a-PMO yields SMN expression at high efficiency in peripheral and CNS tissues, resulting in profound phenotypic correction at doses an order-of-magnitude lower than required by standard naked SSOs. Survival is dramatically extended from 12 d to a mean of 456 d, with improvement in neuromuscular junction morphology, down-regulation of transcripts related to programmed cell death in the spinal cord, and normalization of circulating insulin-like growth factor 1. The potent systemic efficacy of Pip6a-PMO, targeting both peripheral as well as CNS tissues, demonstrates the high clinical potential of peptide-PMO therapy for SMA.spinal muscular atrophy | survival motor neuron | antisense oligonucleotide | splice switching oligonucleotide | cell-penetrating peptide S pinal muscular atrophy (SMA), a leading genetic cause of infant mortality primarily due to lower motor neuron degeneration and progressive muscle weakness, results from loss of the ubiquitous survival motor neuron 1 gene (SMN1) (1, 2). Humans have a second nearly identical copy, SMN2, that differs from SMN1 by a crucial nucleotide transition within exon 7 leading to the predominant generation of an alternative exon 7-excluded transcript and only marginally functional protein (3-7). SMN2 therefore fails to compensate for loss of SMN1 unless sufficient copies are present to generate functional levels of full-length SMN protein (2).A rational, gene therapy-based approach for SMA uses singlestranded antisense splice-switching oligonucleotides (SSOs) to enhance SMN2 pre-mRNA exon 7 inclusion via steric block of splice regulatory pre-mRNA elements (8). Targeting the intron splice silencer N1 (ISS-N1) site within intron 7, by deletion or SSOmediated splice switching, improves exon 7 inclusion (9, 10). ISS-N1-targeted SSOs used to treat presymptomatic severely affected neonatal SMA mice, via systemic or intracerebroventricular administration, extend survival from 10 to >100 d (11, 12). Although SSO targeting to the CNS is essential, there is also evidence for a peripheral role for the SMN in SMA (13-24).Although SSO therapy is currently at an advanced stage of de...

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Alpha‐synuclein protects cerebellar granule neurons against 6‐hydroxydopamine‐induced death

Cited by 53 publications

References 83 publications

Copper-Zinc Superoxide Dismutase (SOD1) Is Released by Microglial Cells and Confers Neuroprotection against 6-OHDA Neurotoxicity

Copper-Zinc Superoxide Dismutase (SOD1) Is Released by Microglial Cells and Confers Neuroprotection against 6-OHDA Neurotoxicity

Peroxidase Mechanism of Lipid-dependent Cross-linking of Synuclein with Cytochrome c

Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy

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