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

ABSTRACT: Parkinson disease (PD) is associated with speech and swallowing difficulties likely due to pathology in widespread brain and nervous system regions. In post-mortem studies of PD, pathology has been reported in pharyngeal and laryngeal nerves and muscles. However, it is unknown whether PD is associated with neuromuscular changes in the tongue. Prior work in a rat model of PD (Pink1-/-) showed oromotor and swallowing deficits in the premanifest stage which suggested sensorimotor impairments of these functions. The present study tested the hypothesis that Pink1-/- rats show altered tongue function coinciding with neuromuscular differences within tongue muscles compared to wildtype (WT). Male Pink1-/- and WT rats underwent behavioral tongue function assays at 4 and 6 months of age (n = 7-8 rats per group), which are time points early in the disease. At 6 months, genioglossus (GG) and styloglossus (SG) muscles were analyzed for myosin heavy chain isoforms (MyHC), ?-synuclein levels, myofiber size, centrally nucleated myofibers, and neuromuscular junction (NMJ) innervation. Pink1-/- showed greater tongue press force variability, and greater tongue press forces and rates as compared to WT. Additionally, Pink1-/- showed relative increases of MyHC 2a in SG, but typical MyHC profiles in GG. Western blots revealed Pink1-/- had more ?-synuclein protein than WT in GG, but not in SG. There were no differences between Pink1-/- and WT in myofiber size, centrally-nucleated myofibers, or NMJ innervation. ?-synuclein protein was observed in nerves, NMJ, and vessels in both genotypes. Findings at these early disease stages suggest small changes or no changes in several peripheral biological measures, and intact motor innervation of tongue muscles. Future work should evaluate these measures at later disease stages to determine when robust pathological peripheral change contributes to functional change, and what CNS deficits cause behavioral changes. Understanding how PD affects central and peripheral mechanisms will help determine therapy targets for speech and swallowing disorders.

SUBMITTER: Glass TJ

PROVIDER: S-EPMC7567376 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Glass Tiffany J TJ Kelm-Nelson Cynthia A CA Szot John C JC Lake Jacob M JM Connor Nadine P NP Ciucci Michelle R MR

PloS one 20201016 10

Parkinson disease (PD) is associated with speech and swallowing difficulties likely due to pathology in widespread brain and nervous system regions. In post-mortem studies of PD, pathology has been reported in pharyngeal and laryngeal nerves and muscles. However, it is unknown whether PD is associated with neuromuscular changes in the tongue. Prior work in a rat model of PD (Pink1-/-) showed oromotor and swallowing deficits in the premanifest stage which suggested sensorimotor impairments of the ...[more]

PMID: 33064741

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Project description:The neural mechanisms underlying behavioral therapy for vocal acoustic deficits in patients with Parkinson disease is unknown. A primary hypothesis is that voice therapy may modulate mesolimbic brainstem regions, including the ventral tegmental area (VTA). The VTA is implicated in ultrasonic call peak frequency, involved in rewarding behaviors, and impacted by Parkinsonism. We tested the hypothesis that chronic (daily) behavioral vocal exercise of male Pink1-/- rats would alter ultrasonic vocalization acoustics and mesolimbic neurochemistry (catecholamines, GABA, mu-opioid receptor) compared to three different controls: sham-exercised Pink1-/-, unexercised Pink1-/-, and unexercised wildtype (WT) rats. A sub-hypothesis is that sham-exercise rats may exhibit changes to VTA neurochemistry as a result of a type or rewarding intervention. Results demonstrate that average bandwidth (frequency range) of ultrasonic vocalizations did not differ between WT, Pink1-/- no exercise vs. sham and vocal-exercise rats. However, average peak frequency is significantly reduced in vocal-exercised Pink1-/- rats compared to Pink1-/- no exercise, and WT groups. Unexpectedly, there were no significant acoustic differences between the vocal- and sham-exercised groups. There were no differences in catecholamine protein concentrations or tyrosine hydroxylase mRNA expression in the VTA between any of the groups. However, there was significant upregulation of all GABA-related genes in both vocal- and sham-exercised Pink1-/- rats (Gad1, Gad2, Gls, Glul); this finding was confirmed with follow up quantitative Western blotting for GAD. Additionally, there were differential results for mu-opioid receptor quantification in the VTA: vocal-exercised Pink1-/- rats showed increased mRNA expression for mu-opioid receptors whereas Western blotting indicated decreased protein levels in all Pink1-/- rats compared to WT controls suggesting the possible onset of pathology in this model. These data demonstrate modulatory effects of a rewarding behavioral paradigm on ultrasonic vocalization peak frequency. The results suggest that neuromodulators such as GABA and opioid activity, as well as the rewarding aspects of therapy may play a key role in shaping vocal treatments.

Project description:Parkinson disease (PD)-affected brains show consistent endoplasmic reticulum (ER) stress and mitophagic dysfunctions. The mechanisms underlying these perturbations and how they are directly linked remain a matter of questions. XBP1 is a transcription factor activated upon ER stress after unconventional splicing by the nuclease ERN1/IREα thereby yielding XBP1s, whereas PINK1 is a kinase considered as the sensor of mitochondrial physiology and a master gatekeeper of mitophagy process. We showed that XBP1s transactivates PINK1 in human cells, primary cultured neurons and mice brain, and triggered a pro-mitophagic phenotype that was fully dependent of endogenous PINK1. We also unraveled a PINK1-dependent phosphorylation of XBP1s that conditioned its nuclear localization and thereby, governed its transcriptional activity. PINK1-induced XBP1s phosphorylation occurred at residues reminiscent of, and correlated to, those phosphorylated in substantia nigra of sporadic PD-affected brains. Overall, our study delineated a functional loop between XBP1s and PINK1 governing mitophagy that was disrupted in PD condition.Abbreviations: 6OHDA: 6-hydroxydopamine; baf: bafilomycin A1; BECN1: beclin 1; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CASP3: caspase 3; CCCP: carbonyl cyanide chlorophenylhydrazone; COX8A: cytochrome c oxidase subunit 8A; DDIT3/CHOP: DNA damage inducible transcript 3; EGFP: enhanced green fluorescent protein; ER: endoplasmic reticulum; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; FACS: fluorescence-activated cell sorting; HSPD1/HSP60: heat shock protein family D (Hsp60) member 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFN2: mitofusin 2; OPTN: optineurin; PD: Parkinson disease; PINK1: PTEN-induced kinase 1; PCR: polymerase chain reaction:; PRKN: parkin RBR E3 ubiquitin protein ligase; XBP1s [p-S61A]: XBP1s phosphorylated at serine 61; XBP1s [p-T48A]: XBP1s phosphorylated at threonine 48; shRNA: short hairpin RNA, SQSTM1/p62: sequestosome 1; TIMM23: translocase of inner mitochondrial membrane 23; TM: tunicamycin; TMRM: tetramethyl rhodamine methylester; TOMM20: translocase of outer mitochondrial membrane 20; Toy: toyocamycin; TP: thapsigargin; UB: ubiquitin; UB (S65): ubiquitin phosphorylated at serine 65; UPR: unfolded protein response, XBP1: X-box binding protein 1; XBP1s: spliced X-box binding protein 1.

Dataset Information

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

Publications

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

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