The involvement of JAK/STAT signaling pathway in the treatment of Parkinson's disease

Lashgari, Naser Aldin; Roudsari, Nazanin Momeni; Momtaz, Saeideh; Sathyapalan, Thozhukat; Abdolghaffari, Amir Hossein; Sahebkar, Amirhossein

doi:10.1016/j.jneuroim.2021.577758

Cited by 50 publications

(16 citation statements)

References 93 publications

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“…The “semaphorin-plexin signaling pathway involved in axon guidance” repression pathway ( Sema3a, Pxnd1, Klk6, Plxnb3 DEGs; FDR < 0.0146) was featured in the A20 group ( Figure 11 a). The dopamine-mediated JAK/STAT pathway gene network reported to be evoked in Parkinson disease [ 32 ] also proved to be elevated specifically in the A20 group ( Jak22, Irs1 DEGs; Figure 11 b). Explicit GO annotation of other GO-enriched categories of the positively regulated 149 DEG cluster in the A20 group is available in Table S5 .…”

Section: Resultsmentioning

confidence: 88%

Dorsal Striatum Transcriptome Profile Profound Shift in Repeated Aggression Mouse Model Converged to Networks of 12 Transcription Factors after Fighting Deprivation

Babenko

Redina

Smagin

et al. 2021

Genes

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Both aggressive and aggression-deprived (AD) species represent pathologic cases intensely addressed in psychiatry and substance abuse disciplines. Previously, we reported that AD mice displayed a higher aggressive behavior score than the aggressive group, implying the manifestation of a withdrawal effect. We employed an animal model of chronic social conflicts, curated in our lab for more than 30 years. In the study, we pursued the task of evaluating key events in the dorsal striatum transcriptome of aggression experienced mice and AD species compared to controls using RNA-Seq profiling. Aggressive species were subjected to repeated social conflict encounters (fights) with regular positive (winners) experience in the course of 20 consecutive days (A20 group). This led to a profoundly shifted transcriptome expression profile relative to the control group, outlined by more than 1000 differentially expressed genes (DEGs). RNA-Seq cluster analysis revealed that elevated cyclic AMP (cAMP) signaling cascade and associated genes comprising 170 differentially expressed genes (DEGs) in aggressive (A20) species were accompanied by a downturn in the majority of other metabolic/signaling gene networks (839 DEGs) via the activation of transcriptional repressor DEGs. Fourteen days of a consecutive fighting deprivation period (AD group) featured the basic restoration of the normal (control) transcriptome expression profile yielding only 62 DEGs against the control. Notably, we observed a network of 12 coordinated DEG Transcription Factor (TF) activators from 62 DEGs in total that were distinctly altered in AD compared to control group, underlining the distinct transcription programs featuring AD group, partly retained from the aggressive encounters and not restored to normal in 14 days. We found circadian clock TFs among them, reported previously as a withdrawal effect factor. We conclude that the aggressive phenotype selection with positive reward effect (winning) manifests an addiction model featuring a distinct opioid-related withdrawal effect in AD group. Along with reporting profound transcriptome alteration in A20 group and gaining some insight on its specifics, we outline specific TF activator gene networks associated with transcriptional repression in affected species compared to controls, outlining Nr1d1 as a primary candidate, thus offering putative therapeutic targets in opioid-induced withdrawal treatment.

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Section: Resultsmentioning

confidence: 88%

Dorsal Striatum Transcriptome Profile Profound Shift in Repeated Aggression Mouse Model Converged to Networks of 12 Transcription Factors after Fighting Deprivation

Babenko

Redina

Smagin

et al. 2021

Genes

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“…Many neurodegenerative disorders, including Parkinson’s disease, are characterized by aberrant activation or phosphorylation of the JAK–STAT signaling pathway. In PD, interferon-gamma (IFN-γ) and IL-6 were found to be two of the most potent activators of the JAK–STAT pathway [ 110 ]. Therefore, dysregulation of the JAK–STAT in PD and its involvement in various inflammatory pathways make it a promising PD therapy approach.…”

Section: Jak–stat Inhibitory Effects Of Quercetin On Neurodegenerativ...mentioning

confidence: 99%

Quercetin as a JAK–STAT inhibitor: a potential role in solid tumors and neurodegenerative diseases

et al. 2022

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The Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway is involved in many immunological processes, including cell growth, proliferation, differentiation, apoptosis, and inflammatory responses. Some of these processes can contribute to cancer progression and neurodegeneration. Owing to the complexity of this pathway and its potential crosstalk with alternative pathways, monotherapy as targeted therapy has usually limited long-term efficacy. Currently, the majority of JAK–STAT-targeting drugs are still at preclinical stages. Meanwhile, a variety of plant polyphenols, especially quercetin, exert their inhibitory effects on the JAK–STAT pathway through known and unknown mechanisms. Quercetin has shown prominent inhibitory effects on the JAK–STAT pathway in terms of anti-inflammatory and antitumor activity, as well as control of neurodegenerative diseases. This review discusses the pharmacological effects of quercetin on the JAK–STAT signaling pathway in solid tumors and neurodegenerative diseases.

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“… 69 - 71 Interestingly, STAT3 signaling is involved in microtubule stabilization in the axonal cytoskeleton of motoneurons. 72 Furthermore, in the neurodegenerative disorder Parkinson’s Disease, the JAK/STAT pathway is dysregulated (reviewed in 73), 73 suggesting a similar effect in SMA and ALS. However, the complexity and association of protein interactions is only partly presented by network approaches.…”

Section: Discussionmentioning

confidence: 99%

Protein Network Analysis Reveals a Functional Connectivity of Dysregulated Processes in ALS and SMA

Kubinski

Claus²

2022

J Exp Neurosci

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Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS) are neurodegenerative diseases which are characterized by the loss of motoneurons within the central nervous system. SMA is a monogenic disease caused by reduced levels of the Survival of motoneuron protein, whereas ALS is a multi-genic disease with over 50 identified disease-causing genes and involvement of environmental risk factors. Although these diseases have different causes, they partially share identical phenotypes and pathomechanisms. To analyze and identify functional connections and to get a global overview of altered pathways in both diseases, protein network analyses are commonly used. Here, we used an in silico tool to test for functional associations between proteins that are involved in actin cytoskeleton dynamics, fatty acid metabolism, skeletal muscle metabolism, stress granule dynamics as well as SMA or ALS risk factors, respectively. In network biology, interactions are represented by edges which connect proteins (nodes). Our approach showed that only a few edges are necessary to present a complex protein network of different biological processes. Moreover, Superoxide dismutase 1, which is mutated in ALS, and the actin-binding protein profilin1 play a central role in the connectivity of the aforementioned pathways. Our network indicates functional links between altered processes that are described in either ALS or SMA. These links may not have been considered in the past but represent putative targets to restore altered processes and reveal overlapping pathomechanisms in both diseases.

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The involvement of JAK/STAT signaling pathway in the treatment of Parkinson's disease

Cited by 50 publications

References 93 publications

Dorsal Striatum Transcriptome Profile Profound Shift in Repeated Aggression Mouse Model Converged to Networks of 12 Transcription Factors after Fighting Deprivation

Dorsal Striatum Transcriptome Profile Profound Shift in Repeated Aggression Mouse Model Converged to Networks of 12 Transcription Factors after Fighting Deprivation

Quercetin as a JAK–STAT inhibitor: a potential role in solid tumors and neurodegenerative diseases

Protein Network Analysis Reveals a Functional Connectivity of Dysregulated Processes in ALS and SMA

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