Lentiviral vector delivery of Parkin prevents dopaminergic degeneration in an α-synuclein rat model of Parkinson's disease

Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2005; 101(50):17510-5. DOI: 10.1073/pnas.0405313101
Source: PubMed


Parkinson's disease (PD) is characterized by a progressive loss of midbrain dopamine neurons and the presence of cytoplasmic inclusions called Lewy bodies. Mutations in several genes including alpha-synuclein and parkin have been linked to familial PD. The loss of parkin's E3-ligase activity leads to dopaminergic neuronal degeneration in early-onset autosomal recessive juvenile parkinsonism, suggesting a key role of parkin for dopamine neuron survival. To evaluate the potential neuroprotective role of parkin in the pathogenesis of PD, we tested whether overexpression of wild-type rat parkin could protect against the toxicity of mutated human A30P alpha-synuclein in a rat lentiviral model of PD. Animals overexpressing parkin showed significant reductions in alpha-synuclein-induced neuropathology, including preservation of tyrosine hydroxylase-positive cell bodies in the substantia nigra and sparing of tyrosine hydroxylase-positive nerve terminals in the striatum. The parkin-mediated neuroprotection was associated with an increase in hyperphosphorylated alpha-synuclein inclusions, suggesting a key role for parkin in the genesis of Lewy bodies. These results indicate that parkin gene therapy may represent a promising candidate treatment for PD.

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Available from: Bernard Schneider
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    • "Parkinson's disease (PD) is the second most common neurodegenerative disease associated to aging (Lo Bianco et al., 2004). Animal and cell models used to study the pathological mechanisms underlying neurodegeneration in PD often involve the administration of toxins that selectively destroy or interrupt the activity of nigrostriatal dopaminergic neurons. "
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    ABSTRACT: Creatine is the substrate for creatine kinase in the synthesis of phosphocreatine (PCr). This energetic system is endowed of antioxidant and neuroprotective properties and plays a pivotal role in brain energy homeostasis. The purpose of this study was to investigate the neuroprotective effect of creatine and PCr against 6-hydroxydopamine (6-OHDA)-induced mitochondrial dysfunction and cell death in rat striatal slices, used as an in vitro Parkinson's model. The possible involvement of the signaling pathway mediated by phosphatidylinositol-3 kinase (PI3K), protein kinase B (Akt), and glycogen synthase kinase-3β (GSK3β) was also evaluated. Exposure of striatal slices to 6-OHDA caused a significant disruption of the cellular homeostasis measured as 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide reduction, lactate dehydrogenase release, and tyrosine hydroxylase levels. 6-OHDA exposure increased the levels of reactive oxygen species and thiobarbituric acid reactive substances production and decreased mitochondrial membrane potential in rat striatal slices. Furthermore, 6-OHDA decreased the phosphorylation of Akt (Serine(473)) and GSK3β (Serine(9)). Coincubation with 6-OHDA and creatine or PCr reduced the effects of 6-OHDA toxicity. The protective effect afforded by creatine or PCr against 6-OHDA-induced toxicity was reversed by the PI3K inhibitor LY294002. In conclusion, creatine and PCr minimize oxidative stress in striatum to afford neuroprotection of dopaminergic neurons. © The Author(s) 2014.
    Full-text · Article · Oct 2014 · ASN Neuro
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    • "Despite the complexity of PD etiology, parkin appears to play a broadly protective role in maintaining neuronal function and viability. These protective effects extend to a variety of neurotoxins, mitochondrial poisons and misfolded proteins including: dopamine [5], rotenone and carbonyl cyanide 3-chlorophenylhydrazone [6], 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), excitotoxin (kainic acid) [7], unfolded protein stress response [8], β-amyloid precursor protein [6], Pael receptor [9], [10], proteasome inhibitors and α-synuclein [11], [12]. Enforced parkin expression also suppresses pathological consequences of PINK1 and DJ-1 gene deficiencies. "
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    ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disorder of complex etiology characterized by the selective loss of dopaminergic neurons, particularly in the substantia nigra. Parkin, a tightly regulated E3 ubiquitin ligase, promotes the survival of dopaminergic neurons in both PD and Parkinsonian syndromes induced by acute exposures to neurotoxic agents. The present study assessed the potential of cell-permeable parkin (CP-Parkin) as a neuroprotective agent. Cellular uptake and tissue penetration of recombinant, enzymatically active parkin was markedly enhanced by the addition of a hydrophobic macromolecule transduction domain (MTD). The resulting CP-Parkin proteins (HPM13 and PM10) suppressed dopaminergic neuronal toxicity in cells and mice exposed to 6-hydroxydopamine (6-OHDH) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These included enhanced survival and dopamine expression in cultured CATH.a and SH-SY5Y neuronal cells; and protection against MPTP-induced damage in mice, notably preservation of tyrosine hydroxylase-positive cells with enhanced dopamine expression in the striatum and midbrain, and preservation of gross motor function. These results demonstrate that CP-Parkin proteins can compensate for intrinsic limitations in the parkin response and provide a therapeutic strategy to augment parkin activity in vivo.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "Parkinson disease (PD), first reported by James Parkinson in 1817, is the second most common neurodegenerative disorder and affects about 2% of the population over the age of 60 [1]. It is characterized by clinical symptoms including rigidity, bradykinesea, resting tremor and postural instability, and by neuropathological features involving loss of dopaminergic (DA) neurons and formation of cytoplasmic lewy bodies in the substantia nigra and substantia innominate [2]. "
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    ABSTRACT: The process of store-operated calcium entry (SOCE), whereby the release of intracellular Ca(2+) from endoplasmic reticulum (ER) activates Ca(2+) influx channels in the plasma membrane, has been demonstrated to impact a diverse range of cell functions. In the present study, we investigated the potential protective effect of SOCE inhibition against 1-methyl-4-phenylpyridinium (MPP(+)) injury by using pharmacological antagonists or specific small interfering RNA (siRNA) in PC12 cells. The results showed that both antagonists (15 μM MRS-1845 and 50 μM ML-9) and stromal interacting molecule-1 (STIM1) targeted siRNA (Si-STIM1) significantly increased cell viability, decreased apoptotic cell death and reduced intracellular reactive oxygen species (ROS) production and lipid peroxidation in MPP(+) injured PC12 cells. SOCE inhibition also prevented MPP(+) induced mitochondrial dysfunction and activation of mitochondrial related apoptotic factors, while had no effect on mitochondrial biogenesis. Moreover, inhibition of SOCE by antagonists and siRNA increased the expression levels of Homer1a mRNA and protein, and knockdown of Homer1a expression by specific siRNA partly reversed the protective effects induced by SOCE inhibition in PC12 cells. All these results indicated that SOCE inhibition protected PC12 cells against MPP(+) insult through upregulation of Homer1a expression, and SOCE might be an ideal target for investigating therapeutic strategy against neuronal injury in PD patients.
    Full-text · Article · Dec 2013 · PLoS ONE
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