Gene expression within the periaqueductal gray is linked to vocal behavior and early-onset parkinsonism in Pink1 knockout rats

Abstract

Background Parkinson’s disease (PD) is a degenerative disease with early-stage pathology hypothesized to manifest in brainstem regions. Vocal deficits, including soft, monotone speech, result in significant clinical and quality of life issues and are present in 90% of PD patients; yet the underlying pathology mediating these significant voice deficits is unknown. The Pink1−/− rat is a valid model of early-onset PD that presents with analogous vocal communication deficits. Previous work shows abnormal α-synuclein protein aggregation in the periaqueductal gray (PAG), a brain region critical and necessary to the modulation of mammalian vocal behavior. In this study, we used high-throughput RNA sequencing to examine gene expression within the PAG of both male and female Pink1−/− rats as compared to age-matched wildtype controls. We used a bioinformatic approach to (1) test the hypothesis that loss of Pink1 in the PAG will influence the differential expression of genes that interact with Pink1, (2) highlight other key genes that relate to this type of Mendelian PD, and (3) catalog molecular targets that may be important for the production of rat vocalizations. Results Knockout of the Pink1 gene resulted in differentially expressed genes for both male and female rats that also mapped to human PD datasets. Pathway analysis highlighted several significant metabolic pathways. Weighted gene co-expression network analysis (WGCNA) was used to identify gene nodes and their interactions in (A) males, (B) females, and (C) combined-sexes datasets. For each analysis, within the module containing the Pink1 gene, Pink1 itself was the central node with the highest number of interactions with other genes including solute carriers, glutamate metabotropic receptors, and genes associated with protein localization. Strong connections between Pink1 and Krt2 and Hfe were found in both males and female datasets. In females a number of modules were significantly correlated with vocalization traits. Conclusions Overall, this work supports the premise that gene expression changes in the PAG may contribute to the vocal deficits observed in this PD rat model. Additionally, this dataset identifies genes that represent new therapeutic targets for PD voice disorders.

The Effect of Maternal Immune Activation on Social Play-Induced Ultrasonic Vocalization in Rats

“…Interestingly, deficient sensory processing has also been reported in MIA models [ 25 ]. Besides, a growing body of evidence has shown that alterations in the periaqueductal gray, a brainstem nucleus engaged in the production of vocalizations and indirect modulation (via motor neurons in the brainstem) of vocal fold vibration, may be the leading cause of impaired communication in mammals [ 48 , 49 ]. Further studies are necessary to answer whether sensory or motor dysfunctions lead to USV alterations and consequently which brain regions (ascending auditory pathway or the periaqueductal gray) are involved in the MIA-induced vocal communication impairment.…”

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

“…The Illumina Stranded Total RNA Library Prep Kit was used to remove rRNA and generate sequencing libraries as described by the manufacturer and in Kelm-Nelson and Gammie, 2020. 46 Sequencing was performed on an HiSeq 2000 high-throughput sequencing system within a single run (Illumina, Inc). After removal of adaptor sequences, contamination and low-quality reads, reads were mapped to the annotated rat (Rattus norvegicus) genome in Ensembl.…”

Predicting Parkinson’s Disease Related Genes Based on PyFeat and Gradient Boosted Decision Tree (GBDT)

“…In addition, KCNJ2, APBB1, and DCTN1 genes are associated with neurodegenerative diseases [42][43][44] . The GJAS gene is related to a gene associated with PD 45 . Finally, the SETX gene is related to the tremor which is determined as a sign of PD 46 .…”