The cross-hemispheric nigrostriatal pathway prevents the expression of levodopa-induced dyskinesias

Iyer, Vishakh; Venkiteswaran, Kala; Savaliya, Sandip; Lieu, Christopher A.; Handly, Erin; Gilmour, Timothy P.; Kunselman, Allen R.; Subramanian, Thyagarajan

doi:10.1016/j.nbd.2021.105491

Cited by 7 publications

(4 citation statements)

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“…In our current work, a cross-modality approach enabled us to show increasing dopaminergic deficits in the putamen and caudate relating to progressive FDG hypometabolism in the left midbrain in a repeated measures design. Although nigrostriatal connections are not exclusively unilateral 36 , 37 , this strong association could arguably be more associative than referring to actual anatomical pathways. Still, this might render additional evidence for a pronounced dopamine depletion in more ventral areas secondary to midbrain degeneration.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal trimodal imaging of midbrain-associated network degeneration in Parkinson’s disease

Steidel

Ruppert

Greuel

et al. 2022

npj Parkinsons Dis.

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The prevailing network perspective of Parkinson’s disease (PD) emerges not least from the ascending neuropathology traceable in histological studies. However, whether longitudinal in vivo correlates of network degeneration in PD can be observed remains unresolved. Here, we applied a trimodal imaging protocol combining 18F-fluorodeoxyglucose (FDG)- and 18F-fluoro-L-Dopa- (FDOPA)-PET with resting-state functional MRI to assess longitudinal changes in midbrain metabolism, striatal dopamine depletion and striatocortical dysconnectivity in 17 well-characterized PD patients. Whole-brain (un)paired-t-tests with focus on midbrain or striatum were performed between visits and in relation to 14 healthy controls (HC) in PET modalities. Resulting clusters of FDOPA-PET comparisons provided volumes for seed-based functional connectivity (FC) analyses between visits and in relation to HC. FDG metabolism in the left midbrain decreased compared to baseline along with caudatal FDOPA-uptake. This caudate cluster exhibited a longitudinal FC decrease to sensorimotor and frontal areas. Compared to healthy subjects, dopamine-depleted putamina indicated stronger decline in striatocortical FC at follow-up with respect to baseline. Increasing nigrostriatal deficits and striatocortical decoupling were associated with deterioration in motor scores between visits in repeated-measures correlations. In summary, our results demonstrate the feasibility of in-vivo tracking of progressive network degeneration using a multimodal imaging approach. Specifically, our data suggest advancing striatal and widespread striatocortical dysfunction via an anterior-posterior gradient originating from a hypometabolic midbrain cluster within a well-characterized and only mild to moderately affected PD cohort during a relatively short period.

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Section: Discussionmentioning

confidence: 99%

Longitudinal trimodal imaging of midbrain-associated network degeneration in Parkinson’s disease

Steidel

Ruppert

Greuel

et al. 2022

npj Parkinsons Dis.

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“…We can observe in the intact side of the transplanted groups a signi cant increase of Th expression in comparison with the Sham group; this effect has been attributed to a cross hemispheric nigrostriatal branching that occurs in the unilateral 6-OHDA lesion on the MFB, so dopaminergic bers migrate to the contralateral striatum. (41,42) Expression of Th and GFAP in the lesioned striata. This series of experiments aimed to show the expression of in the implanted astrocytes.…”

Section: Resultsmentioning

confidence: 99%

CRISPR/sgRNA-directed synergistic activation mediator (SAM) as a therapeutic tool for Parkinson´s disease

Narvaez-Perez

Paz‐Bermúdez

Ávalos-Fuentes

et al. 2023

Preprint

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Parkinson`s disease (PD) is the second most prevalent neurodegenerative disease, and different gene therapy strategies have been used as experimental treatments. As a proof of concept for the treatment of PD, we used SAM, a CRISPR gene activation system, to activate the endogenous tyrosine hydroxylase gene of astrocytes to produce dopamine (DA) in the striatum of 6-OHDA-lesioned rats. Potential sgRNAs within the rat th promotor region were tested, the expression of the Th protein was determined in the C6 glial cell line. Employing pseudo-lentivirus, the SAM complex and the selected sgRNA were transferred into cultures of rat astrocytes, and gene expression and Th protein synthesis were ascertained; furthermore, DA release into the culture medium was determined by HPLC. The DA-producing astrocytes were implanted into the striatum of 6-OHDA hemiparkinsonian rats. We observed motor behavior improvement in the lesioned rats that received DA-astrocytes compared to lesioned rats receiving astrocytes that did not produce DA. There were no differences between the DA-producing astrocytes group compared to the Sham (non-lesioned group) on the motor behavior tests. Our data indicate that the SAM-induced expression of the astrocyte´s endogenous th gene can generate DA-producing astrocytes that effectively reduce motor symptoms in a rat PD model.

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“…On the other hand, caudate and putamen (which compose the dorsal striatum) had the highest expression level of upregulated-EASR genes. The striatum is connected to the substantia nigra through the nigrostriatal pathway, one of the four major dopamine pathways (Iyer et al, 2021). However, unlike the substantia nigra, it has been reported that oxidative damage and mitochondrial dysfunction in the striatum (caudate and putamen) were lower in the PD brains (Venkateshappa et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Characterization of exogenous αSN response genes and their relation to Parkinson’s disease using network analyses

Nayeri

Aliakbari²,

Afzali³

et al. 2022

Front. Pharmacol.

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Despite extensive research, the molecular mechanisms underlying the toxicity of αSN in Parkinson’s disease (PD) pathology are still poorly understood. To address this, we used a microarray dataset to identify genes that are induced and differentially expressed after exposure to toxic αSN aggregates, which we call exogenous αSN response (EASR) genes. Using systems biology approaches, we then determined, at multiple levels of analysis, how these EASR genes could be related to PD pathology. A key result was the identification of functional connections between EASR genes and previously identified PD-related genes by employing the proteins’ interactions networks and 9 brain region-specific co-expression networks. In each brain region, co-expression modules of EASR genes were enriched for gene sets whose expression are altered by SARS-CoV-2 infection, leading to the hypothesis that EASR co-expression genes may explain the observed links between COVID-19 and PD. An examination of the expression pattern of EASR genes in different non-neurological healthy brain regions revealed that regions with lower mean expression of the upregulated EASR genes, such as substantia nigra, are more vulnerable to αSN aggregates and lose their neurological functions during PD progression. Gene Set Enrichment Analysis of healthy and PD samples from substantia nigra revealed that a specific co-expression network, “TNF-α signaling via NF-κB”, is an upregulated pathway associated with the PD phenotype. Inhibitors of the “TNF-α signaling via NF-κB” pathway may, therefore, decrease the activity level of this pathway and thereby provide therapeutic benefits for PD patients. We virtually screened FDA-approved drugs against these upregulated genes (NR4A1, DUSP1, and FOS) using docking-based drug discovery and identified several promising drugs. Altogether, our study provides a better understanding of αSN toxicity mechanisms in PD and identifies potential therapeutic targets and small molecules for treatment of PD.

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The cross-hemispheric nigrostriatal pathway prevents the expression of levodopa-induced dyskinesias

Cited by 7 publications

References 100 publications

Longitudinal trimodal imaging of midbrain-associated network degeneration in Parkinson’s disease

Longitudinal trimodal imaging of midbrain-associated network degeneration in Parkinson’s disease

CRISPR/sgRNA-directed synergistic activation mediator (SAM) as a therapeutic tool for Parkinson´s disease

Characterization of exogenous αSN response genes and their relation to Parkinson’s disease using network analyses

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