Abstract
BackgroundParkinson’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.ResultsKnockout 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.ConclusionsOverall, 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.
Highlights
Parkinson’s disease (PD) is a degenerative disease with early-stage pathology hypothesized to manifest in brainstem regions
We tested the specific hypotheses: [1] loss of Pink1 in the periaqueductal gray (PAG) will influence expression of genes that interact with Pink1 [2]; loss of Pink1 will emphasize other genes that relate to PD; and [3] behavioral and bioinformatic approaches to data analysis will identify molecular targets important for rat vocalization
We have shown that glutamate decarboxylase 1 (Gad1) in the PAG is significantly reduced in Pink1−/− rats [58] and our most recent work suggests that modulation of the GABA neurotransmitter represents therapeutic targets for rescuing vocalization
Summary
Parkinson’s disease (PD) is a degenerative disease with early-stage pathology hypothesized to manifest in brainstem regions. Vocal communication deficits, including hypokinetic dysarthria [5,6,7,8], are common and during the course of disease progression, over 90% of individuals present with these deficits These signs negatively influence overall health, social interactions, employment, and quality of life [6, 7, 9, 10]. Despite this considerable clinical issue, the underlying central nervous system pathology that contributes to vocalization deficits in PD is poorly understood and understudied. Functional imaging studies demonstrate that the brainstem PAG is involved in the circuitry and control of speech [22], and appears to be involved in the speech patterns of individuals with PD (where PAG connectivity is correlated to speech loudness) [23]
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