Functional characterization of extrinsic tongue muscles in the Pink1-/- rat model of Parkinson disease

Glass, Tiffany J.; Kelm‐Nelson, Cynthia A.; Szot, John; Lake, Jacob M.; Connor, Nadine P.; Ciucci, Michelle R.

doi:10.1371/journal.pone.0240366

Cited by 12 publications

(5 citation statements)

References 49 publications

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“…17,19 Increases in alpha-synuclein within the neuromuscular junction, nerves and vessels of 6 month old Pink1À/À rats have been reported in the extrinsic tongue muscle (genioglossus) and has been hypothesized to be a small, disease occurring change in the innervation of the tongue muscles. 60 A key interpretation of the current study is that changes in gene pathways (e.g., kallikrein and/or inflammatory pathways) maybe significant in this early disease model, lead to muscle pathology, and therefore, warrants further investigation.…”

Section: Discussionmentioning

confidence: 86%

Thyroarytenoid Muscle Gene Expression in a Rat Model of Early‐Onset Parkinson's Disease

et al. 2021

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Objectives/Hypothesis: Voice disorders in Parkinson's disease (PD) are early-onset, manifest in the preclinical stages of the disease, and negatively impact quality of life. The complete loss of function in the PTEN-induced kinase 1 gene (Pink1) causes a genetic form of early-onset, autosomal recessive PD. Modeled after the human inherited mutation, the Pink1À/À rat demonstrates significant cranial sensorimotor dysfunction including declines in ultrasonic vocalizations. However, the underlying genetics of the vocal fold thyroarytenoid (TA) muscle that may contribute to vocal deficits has not been studied. The aim of this study was to identify differentially expressed genes in the TA muscle of 8-month-old male Pink1À/À rats compared to wildtype controls.Study Design: Animal experiment with control. Methods: High throughput RNA sequencing was used to examine TA muscle gene expression in adult male Pink1À/À rats and wildtype controls. Weighted Gene Co-expression Network Analysis was used to construct co-expression modules to identify biological networks, including where Pink1 was a central node. The ENRICHR tool was used to compare this gene set to existing human gene databases.Results: We identified 134 annotated differentially expressed genes (P < .05 cutoff) and observed enrichment in the following biological pathways: Parkinson's disease (Casp7, Pink1); Parkin-Ubiquitin proteasome degradation (Psmd12, Psmd7); MAPK signaling (Casp7, Ppm1b, Ppp3r1); and inflammatory TNF-α, Nf-κB Signaling (Casp7, Psmd12, Psmd7, Cdc34, Bcl7a, Peg3).Conclusions: Genes and pathways identified here may be useful for evaluating the specific mechanisms of peripheral dysfunction including within the laryngeal muscle and have potential to be used as experimental biomarkers for treatment development.

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Section: Discussionmentioning

confidence: 86%

Thyroarytenoid Muscle Gene Expression in a Rat Model of Early‐Onset Parkinson's Disease

et al. 2021

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“…In the context of the present study, loss of Pink1 may lead to increased pathologic alpha‐synuclein in the peripheral head and neck muscles, including the TA, which interferes with the SNARE complex and has a detrimental effect on synaptic vesicle fusion and exocytosis. Moreover, aggregation within the laryngeal/pharyngeal structures has been shown in humans with late‐stage PD 13,14 and in Pink1 −/− rats, alpha‐synuclein was detected in tongue muscles 74 . Dysfunction in exocytosis/endocytosis and synaptic vesicle function may underlie muscle function in PD and is yet to be studied in this rat model.…”

Section: Discussionmentioning

confidence: 91%

“…Moreover, aggregation within the laryngeal/pharyngeal structures has been shown in humans with late-stage PD 13,14 and in Pink1À/À rats, alpha-synuclein was detected in tongue muscles. 74 Dysfunction in exocytosis/endocytosis and synaptic vesicle function may underlie muscle function in PD and is yet to be studied in this rat model. Female Pink1À/À Rats Demonstrate a Significantly Higher Number of Dysregulated Genes and Pathways Compared with Male Pink1À/À Rats Several downregulated genes in male TA muscles were found to be upregulated in females.…”

Section: Synaptic Signaling and Calcium-dependent Exocytosis Of Neuro...mentioning

confidence: 99%

Thyroarytenoid Oxidative Metabolism and Synaptic Signaling Dysregulation in the Female Pink1−/− Rat

et al. 2023

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Objectives and hypothesisVocal dysfunction, including hypophonia, in Parkinson disease (PD) manifests in the prodromal period and significantly impacts an individual's quality of life. Data from human studies suggest that pathology leading to vocal deficits may be structurally related to the larynx and its function. The Pink1−/− rat is a translational model used to study pathogenesis in the context of early‐stage mitochondrial dysfunction. The primary objective of this work was to identify differentially expressed genes in the thyroarytenoid muscle and examine the dysregulated biological pathways in the female rat.MethodsRNA sequencing was used to determine thyroarytenoid (TA) muscle gene expression in adult female Pink1−/− rats compared with controls. A bioinformatic approach and the ENRICHR gene analysis tool were used to compare the sequencing dataset with biological pathways and processes, disease relationships, and drug‐repurposing compounds. Weighted Gene Co‐expression Network Analysis was used to construct biological network modules. The data were compared with a previously published dataset in male rats.ResultsSignificant upregulated pathways in female Pink1−/− rats included fatty acid oxidation and muscle contraction, synaptic transmission, and neuromuscular processes. Downregulated pathways included anterograde transsynaptic signaling, chemical synaptic transmission, and ion release. Several drug treatment options including cetuximab, fluoxetine, and resveratrol are hypothesized to reverse observed genetic dysregulation.ConclusionsData presented here are useful for identifying biological pathways that may underlie the mechanisms of peripheral dysfunction including neuromuscular synaptic transmission to the TA muscle. These experimental biomarkers have the potential to be targeted as sites for improving the treatment for hypophonia in early‐stage PD.Level of EvidenceN/A Laryngoscope, 2023

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“…Differentiation oromotor signs in clinical stages may also facilitate optimizing the dopamine replacement therapies 43 and planning the site of deep brain stimulation 44 . Muscle-strengthening, movement-range and sensory-perceptual exercises improve lingual-wave delay and/or bolus control in oral phase 5,45 due central-peripheral mechanisms instead of muscular changes 46 . Intensive voice treatment (LSVT) targeting tongue root movement may improve coordination between breathing and swallowing or airway protection 47 .…”

Section: Discussionmentioning

confidence: 99%

Subtle oromotor signs in early Parkinson’s disease before clinical manifestations of dysphagia

Gudwani

Upadhyay

Sharma

et al. 2021

Preprint

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Background: Swallowing is complex phenomena comprising oral (preparatory and pre-swallow positioning), oropharyngeal, pharyngeal and esophageal phases. The timing of these phases is controlled by brain stem pattern generators including reflex for oropharyngeal propulsion and transit. Dysphagia in Parkinson's disease (PD) commonly observed at late stages with aspiration, pneumonia and hospitalization. Objective: Can subtle oromotor signs (if any) be observed for planning early interventions in PD Methods: The present study investigated oromotor function in fourteen early PD (onset ≤2years; H&Y ≤2.5) with dynamic MRI using saline (water) bolus and compared with seven age-matched healthy controls. Results: All the patients with PD were non-symptomatic for dysphagia by self-reporting, and on clinical assessment (Part-II MDS-UPDRS, Swallowing disturbance questionnaire, SDQ and Clinical assessment of dysphagia in neurodegeneration, CADN). Qualitatively MR images visualized, differences in PD compared to healthy controls for tongue-wave, velar-closure or release, bolus placement, oropharyngeal reflex-initiation, transit-time, epiglottic-closure-coordination and post-swallow oral or pharyngeal residue. Descriptive analysis showed higher variability of velar-closure, oropharyngeal- and pharygoesophageal-transit time in patient with PD. Group analysis (two-sample) show significant difference for velar-closure. Conclusion: Multiple lingual-waves, reverse-tongue thrust, with delayed velar control attributed to incoordinated muscular rhythm. Variable oropharyngeal transit time (0.64 to 2.25 msec) in PD ascribed to brainstem degenerative changes. Findings imply that subtle observable early oromotor signs as pre-clinical manifestation when evaluated with non-invasive, non-contrast dynamic MRI support early intervention, to prevent late-stage aspiration episodes and consequent hospitalizations.

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Functional characterization of extrinsic tongue muscles in the Pink1-/- rat model of Parkinson disease

Cited by 12 publications

References 49 publications

Thyroarytenoid Muscle Gene Expression in a Rat Model of Early‐Onset Parkinson's Disease

Thyroarytenoid Muscle Gene Expression in a Rat Model of Early‐Onset Parkinson's Disease

Thyroarytenoid Oxidative Metabolism and Synaptic Signaling Dysregulation in the Female Pink1−/− Rat

Subtle oromotor signs in early Parkinson’s disease before clinical manifestations of dysphagia

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