Exogenous protein HSP70 blocks neurodegeneration in the rat model of the clinical stage of Parkinson’s disease

Pastukhov, Yu. F.; Plaksina, D. V.; Lapshina, K. V.; Guzhova, Irina V.; Екимова, И. В.

doi:10.1134/s0012496614040139

Cited by 15 publications

(8 citation statements)

References 11 publications

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“…8B). All but one of these hubs have been implicated in PD: AKT1 (37 edges) 70,71 , HGS (26 edges), CDC37/HSP90 (22 edges) 72,73 , STUB1/CHIP (20 edges) 74 , and HSPA1A (22 edges) 75–77 (Fig. 7B).…”

Section: Resultsmentioning

confidence: 99%

Neural Stem Cells Derived from Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson's Disease

Gonzalez¹,

Garitaonandia²,

Poustovoitov³

et al. 2016

Cell Transplant

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Cell therapy has attracted considerable interest as a promising therapeutic alternative for patients with Parkinson's disease (PD). Clinical studies have shown that grafted fetal neural tissue can achieve considerable biochemical and clinical improvements in PD. However, the source of fetal tissue grafts is limited and ethically controversial. Human parthenogenetic stem cells offer a good alternative because they are derived from unfertilized oocytes without destroying potentially viable human embryos and can be used to generate an unlimited supply of neural cells for transplantation. We have previously reported that human parthenogenetic stem cellderived neural stem cells (hpNSCs) successfully engraft, survive long term, and increase brain dopamine (DA) levels in rodent and nonhuman primate models of PD. Here we report the results of a 12-month transplantation study of hpNSCs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned African green monkeys with moderate to severe clinical parkinsonian symptoms. The hpNSCs manufactured under current good manufacturing practice (cGMP) conditions were injected bilaterally into the striatum and substantia nigra of immuno suppressed monkeys. Transplantation of hpNSCs was safe and well tolerated by the animals with no dyskinesia, tumors, ectopic tissue formation, or other test article-related serious adverse events. We observed that hpNSCs promoted behavioral recovery; increased striatal DA concentration, fiber innervation, and number of dopaminergic neurons; and induced the expression of genes and pathways downregulated in PD compared to vehicle control animals. These results provide further evidence for the clinical translation of hpNSCs and support the approval of the world's first pluripotent stem cell-based phase I/IIa study for the treatment of PD (Clinical Trial Identifier NCT02452723).

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Section: Resultsmentioning

confidence: 99%

Neural Stem Cells Derived from Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson's Disease

Gonzalez¹,

Garitaonandia²,

Poustovoitov³

et al. 2016

Cell Transplant

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“…In addition, it has been demonstrated that mutation in these genes also relate to onset of manganism [18–20]. As a putative treatment, recently, studies provided evidence on the important role of HSP70 in recovering DAergic neurons or degrading misfolded proteins in PD models [21, 22]. …”

Section: Introductionmentioning

confidence: 99%

Involvement of heat shock proteins on Mn-induced toxicity in Caenorhabditis elegans

Ávila

Benedetto

et al. 2016

BMC Pharmacol Toxicol

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BackgroundAll living cells display a rapid molecular response to adverse environmental conditions, and the heat shock protein family reflects one such example. Hence, failing to activate heat shock proteins can impair the cellular response. In the present study, we evaluated whether the loss of different isoforms of heat shock protein (hsp) genes in Caenorhabditis elegans would affect their vulnerability to Manganese (Mn) toxicity.MethodsWe exposed wild type and selected hsp mutant worms to Mn (30 min) and next evaluated further the most susceptible strains. We analyzed survival, protein carbonylation (as a marker of oxidative stress) and Parkinson’s disease related gene expression immediately after Mn exposure. Lastly, we observed dopaminergic neurons in wild type worms and in hsp-70 mutants following Mn treatment. Analysis of the data was performed by one-way or two way ANOVA, depending on the case, followed by post-hoc Bonferroni test if the overall p value was less than 0.05.ResultsWe verified that the loss of hsp-70, hsp-3 and chn-1 increased the vulnerability to Mn, as exposed mutant worms showed lower survival rate and increased protein oxidation. The importance of hsp-70 against Mn toxicity was then corroborated in dopaminergic neurons, where Mn neurotoxicity was aggravated. The lack of hsp-70 also blocked the transcriptional upregulation of pink1, a gene that has been linked to Parkinson’s disease.ConclusionsTaken together, our data suggest that Mn exposure modulates heat shock protein expression, particularly HSP-70, in C. elegans. Furthermore, loss of hsp-70 increases protein oxidation and dopaminergic neuronal degeneration following manganese exposure, which is associated with the inhibition of pink1 increased expression, thus potentially exacerbating the vulnerability to this metal.

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“…HSP70-related anti-fibrillation may have contributed to the protection of dopaminergic neurons in MANF-treated cells and PD animals [28]. Earlier studies have shown that the aggregation ofα-Synuclein is linked to the pathogenesis of PD.…”

Section: Discussionmentioning

confidence: 99%

Mesencephalic astrocyte-derived neurotrophic factor reduces cell apoptosis via upregulating HSP70 in SHSY-5Y cells

Sun

Jiang

et al. 2017

Transl Neurodegener

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BackgroundMesencephalic astrocyte-derived neurotrophic factor (MANF) is a new candidate growth factor for dopaminergic neurons against endoplasmic reticulum stress (ER stress). HSP70 family, a chaperon like heat shock protein family, was proved to be involved in the MANF induced survival pathway in 6-OHDA treated SHSY-5Y cells. However, the ER stress relative transcriptome, in MANF signaling cascades is still investigated. The involvement of HSP70, a 70kd member of HSP70 family, need further to be verified.MethodsThe cell apoptosis was assayed by MTT, TUNEL staining and western blot of cleaved Caspase-3. The differentially expressed genes in SHSY-5Y cells under different conditions (control, 6-OHDA, 6-OHDA + MANF) were investigated by RNA-seq. Expression of HSP70 was further confirmed by real-time PCR. RNAi knockdown for HSP70 was performed to investigate the role of HSP70 in the MANF signaling pathway.ResultsMANF inhibits 6-OHDA-induced apoptosis in SHSY-5Y cells. Six ER stress relative genes (HSP70, GRP78, xbp-1, ATF-4, ATF-6, MAPK) were found enriched in 6-OHDA + MANF treatment group. HSP70 was the most significantly up-regulated gene under 6-OHDA + MANF treatment in SHSY-5Y cells. RNAi knockdown for HSP70 inhibits the protective effects of MANF against 6-OHDA toxicity in SHSY-5Y cells.ConclusionMANF exerts a protective role against 6-OHDA induced apoptosis in SHSY-5Y cells via up-regulating some ER stress genes, including HSP70 family members. The HSP70 expression level plays a key role in MANF-mediated survival pathway.

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Exogenous protein HSP70 blocks neurodegeneration in the rat model of the clinical stage of Parkinson’s disease

Cited by 15 publications

References 11 publications

Neural Stem Cells Derived from Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson's Disease

Neural Stem Cells Derived from Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson's Disease

Involvement of heat shock proteins on Mn-induced toxicity in Caenorhabditis elegans

Mesencephalic astrocyte-derived neurotrophic factor reduces cell apoptosis via upregulating HSP70 in SHSY-5Y cells

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