Modulation of excessive neuronal activity by fibroblasts: Potential use in treatment of Parkinson's disease

Finberg, J. P. M.; Gluzman, Zoya; Reshef, Michal; Loboda, Yelena; Mohsen, Usama; Bressler-Stramer, Tal; Miari, Reem; Gepstein, Lior; Marom, Shimon; Feld, Yair

doi:10.3233/rnn-2010-0551

Cited by 2 publications

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“…The dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA, 8 µg) or saline (control) were injected to the left medial forebrain bundle of Sprague-Dawley male rats one, three or seven days previous to whole-body perfusion fixation with paraformaldehyde. Coronal cryostat sections (30 μ) were stained with TUNEL reagent or by immunofluorescence (IF) assay using polyclonal anti-ARTS or monoclonal anti-cleaved caspase-3 as primary antibodies [50]. Sections were viewed using a UV microscope equipped with high-resolution digital camera, and photomicrographs were made of the substantia nigra pars compacta area (identified by presence of large dopaminergic cell-bodies) at a level corresponding to bregma -4.8–4.9 according to previously ascertained topographical markers.…”

Section: Methodsmentioning

confidence: 99%

Parkin Promotes Degradation of the Mitochondrial Pro-Apoptotic ARTS Protein

et al. 2012

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Parkinson’s disease (PD) is associated with excessive cell death causing selective loss of dopaminergic neurons. Dysfunction of the Ubiquitin Proteasome System (UPS) is associated with the pathophysiology of PD. Mutations in Parkin which impair its E3-ligase activity play a major role in the pathogenesis of inherited PD. ARTS (Sept4_i2) is a mitochondrial protein, which initiates caspase activation upstream of cytochrome c release in the mitochondrial apoptotic pathway. Here we show that Parkin serves as an E3-ubiquitin ligase to restrict the levels of ARTS through UPS-mediated degradation. Though Parkin binds equally to ARTS and Sept4_i1 (H5/PNUTL2), the non-apoptotic splice variant of Sept4 , Parkin ubiquitinates and degrades only ARTS. Thus, the effect of Parkin on ARTS is specific and probably related to its pro-apoptotic function. High levels of ARTS are sufficient to promote apoptosis in cultured neuronal cells, and rat brains treated with 6-OHDA reveal high levels of ARTS. However, over-expression of Parkin can protect cells from ARTS-induced apoptosis. Furthermore, Parkin loss-of-function experiments reveal that reduction of Parkin causes increased levels of ARTS and apoptosis. We propose that in brain cells in which the E3-ligase activity of Parkin is compromised, ARTS levels increase and facilitate apoptosis. Thus, ARTS is a novel substrate of Parkin. These observations link Parkin directly to a pro-apoptotic protein and reveal a novel connection between Parkin, apoptosis, and PD.

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Section: Methodsmentioning

confidence: 99%

Parkin Promotes Degradation of the Mitochondrial Pro-Apoptotic ARTS Protein

et al. 2012

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Effects of fibroblast transplantation into the internal pallidum on levodopa-induced dyskinesias in parkinsonian non-human primates

Singh¹,

Gutekunst

Uthayathas³

et al. 2015

Neurosci. Bull.

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Recent studies have shown that fibroblast transplantation can modify the activity of basal ganglia networks in models of Parkinson’s disease. To determine its effects on parkinsonian motor symptoms, we performed autologous dermal fibroblast transplantation into the internal pallidum (GPi) in two parkinsonian rhesus monkeys with stable levodopa-induced dyskinesias (LIDs). Levodopa responses were assessed every week after transplantation for three months. A reduction of between 58% and 64% in total LIDs on the contralateral side was observed in both animals. No clear LID changes were observed on the ipsilateral side. These effects lasted the entire 3-month period in one monkey, but declined after 6–8 weeks in the other. The antiparkinsonian effects of levodopa did not diminish. The results of this pilot study indicate that fibroblast transplantation into the GPi may have beneficial effects on LIDs and warrant further investigation for potential therapeutic use.

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Modulation of excessive neuronal activity by fibroblasts: Potential use in treatment of Parkinson's disease

Cited by 2 publications

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Parkin Promotes Degradation of the Mitochondrial Pro-Apoptotic ARTS Protein

Parkin Promotes Degradation of the Mitochondrial Pro-Apoptotic ARTS Protein

Effects of fibroblast transplantation into the internal pallidum on levodopa-induced dyskinesias in parkinsonian non-human primates

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