Role of striatal ΔFosB in
            <scp>l</scp>
            -Dopa–induced dyskinesias of parkinsonian nonhuman primates

Beck, Goichi; Singh, Anneliese A.; Zhang, Jie; Potts, Lisa F.; Woo, Jong Min; Park, Eun Su; Mochizuki, Hideki; Mouradian, M. Maral; Papa, Stella M.

doi:10.1073/pnas.1907810116

Cited by 25 publications

(25 citation statements)

References 37 publications

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“…In the present study, up to the 1, 4, and 17 months after the treatment with the α-syn PFFs, we did not observe dopaminergic neuron loss in the substantia nigra, nor motor and cognitive dysfunction (Supplementary Fig. 7 ) in consistent with the previous report 43 , but rather, only detected signs of dopaminergic neurodegeneration, i.e., reduced TH intensity and axonal swelling in the putamen 44 – 46 . Interestingly, an increase in the iron content was detected in the brains of monkeys in the PD model groups and further studies revealed that the increased iron was mainly deposited in the substantia nigra and globus pallidus, which are also the brain regions that exhibit lesions in PD patients 47 – 51 .…”

Section: Discussionsupporting

confidence: 93%

Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis

et al. 2021

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Iron deposition is present in main lesion areas in the brains of patients with Parkinson’s disease (PD) and an abnormal iron content may be associated with dopaminergic neuronal cytotoxicity and degeneration in the substantia nigra of the midbrain. However, the cause of iron deposition and its role in the pathological process of PD are unclear. In the present study, we investigated the effects of the nasal mucosal delivery of synthetic human α-synuclein (α-syn) preformed fibrils (PFFs) on the pathogenesis of PD in Macaca fascicularis. We detected that iron deposition was clearly increased in a time-dependent manner from 1 to 17 months in the substantia nigra and globus pallidus, highly contrasting to other brain regions after treatments with α-syn PFFs. At the cellular level, the iron deposits were specifically localized in microglia but not in dopaminergic neurons, nor in other types of glial cells in the substantia nigra, whereas the expression of transferrin (TF), TF receptor 1 (TFR1), TF receptor 2 (TFR2), and ferroportin (FPn) was increased in dopaminergic neurons. Furthermore, no clear dopaminergic neuron loss was observed in the substantia nigra, but with decreased immunoreactivity of tyrosine hydroxylase (TH) and appearance of axonal swelling in the putamen. The brain region-enriched and cell-type-dependent iron localizations indicate that the intranasal α-syn PFFs treatment-induced iron depositions in microglia in the substantia nigra may appear as an early cellular response that may initiate neuroinflammation in the dopaminergic system before cell death occurs. Our data suggest that the inhibition of iron deposition may be a potential approach for the early prevention and treatment of PD.

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Section: Discussionsupporting

confidence: 93%

Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis

et al. 2021

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“…In Parkinsonian rat, local administration of L -DOPA in the striatum induces dyskinesia ( Buck et al, 2010 ). Further immediate-early genes such as c-Fos, FosB, and ΔFosB are consistently upregulated in the striatum of animals with LID ( Cenci, 2002 ; Beck et al, 2019 ). Detailed information about the involvement of the striatum in LID can be found in other articles ( Cenci et al, 2018 ; Zhai et al, 2019 ).…”

Section: Possible Loci Of Circuit Modulation In Lidmentioning

confidence: 99%

Circuit Mechanisms of L-DOPA-Induced Dyskinesia (LID)

et al. 2021

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L-DOPA is the criterion standard of treatment for Parkinson disease. Although it alleviates some of the Parkinsonian symptoms, long-term treatment induces L-DOPA–induced dyskinesia (LID). Several theoretical models including the firing rate model, the firing pattern model, and the ensemble model are proposed to explain the mechanisms of LID. The “firing rate model” proposes that decreasing the mean firing rates of the output nuclei of basal ganglia (BG) including the globus pallidus internal segment and substantia nigra reticulata, along the BG pathways, induces dyskinesia. The “firing pattern model” claimed that abnormal firing pattern of a single unit activity and local field potentials may disturb the information processing in the BG, resulting in dyskinesia. The “ensemble model” described that dyskinesia symptoms might represent a distributed impairment involving many brain regions, but the number of activated neurons in the striatum correlated most strongly with dyskinesia severity. Extensive evidence for circuit mechanisms in driving LID symptoms has also been presented. LID is a multisystem disease that affects wide areas of the brain. Brain regions including the striatum, the pallidal–subthalamic network, the motor cortex, the thalamus, and the cerebellum are all involved in the pathophysiology of LID. In addition, although both amantadine and deep brain stimulation help reduce LID, these approaches have complications that limit their wide use, and a novel antidyskinetic drug is strongly needed; these require us to understand the circuit mechanism of LID more deeply.

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“…Among others, This transcription factor regulates genes responsible for plasticity in striatal neurons. Elevated levels of ΔFosB are associated with loss of function of FosB, which results in early development of dyskinesia and unstable firing rate changes during ON phase in L-DOPA treated animals [69]. MSH1 histone kinase activity also increases with ΔFosB levels, consistent with MSK1's target, histone H3.…”

Section: Fosb Transcription Factormentioning

confidence: 71%

Current Knowledge on the Background, Pathophysiology, and Treatment of Levodopa-Induced Dyskinesia – Literature Review.

Hutny¹,

Hofman²,

Klimkowicz‐Mrowiec³

et al. 2021

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Levodopa remains the primary drug for controlling motor symptoms in Parkinson's disease through the whole course, but over time complications develop in the form of dyskinesias, which gradually become more frequent and severe. These abnormal, involuntary, hyperkinetic movements are mostly characteristic of the ON phase and reflect an excess of exogenous levodopa. They may also occur during OFF phase, or in both phases. Over the past 10 years, the issue of levodopa-induced dyskinesia has been the subject of research into both the substrate of this pathology and potential remedial strategies. The purpose of the present study was to review the results of recent research on the background and treatment of dyskinesia. To this end, databases were reviewed using a search strategy that included both relevant keywords related to the topic and appropriate filters to limit results to English-language literature published since 2010. Based on the selected papers, the current state of knowledge on morphological, functional, genetic, and clinical features of levodopa-induced dyskinesia, as well as pharmacological, genetic treatment and other therapies such as deep brain stimulation are described.

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Role of striatal ΔFosB in l -Dopa–induced dyskinesias of parkinsonian nonhuman primates

Cited by 25 publications

References 37 publications

Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis

Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis

Circuit Mechanisms of L-DOPA-Induced Dyskinesia (LID)

Current Knowledge on the Background, Pathophysiology, and Treatment of Levodopa-Induced Dyskinesia – Literature Review.

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