Predictors of prodromal Parkinson’s disease in young adult Pink1−/− rats

Abstract

Parkinson’s disease (PD) is a progressive, degenerative disease that affects nearly 10 million people worldwide. Hallmark limb motor signs and dopamine depletion have been well studied; however, few studies evaluating early stage, prodromal biology exist. Pink1−/− rats, a rodent model of PD mitochondrial dysfunction, exhibit early stage behavioral deficits, including vocal communication and anxiety, that progress during mid-to-late adulthood (6–12 months of age). Yet, the biological pathways and mechanisms that lead to prodromal dysfunction are not well understood. This study investigated the Pink1−/− rat in young adulthood (2 months of age). Mixed sex groups of Pink1−/− rats and wildtype (WT) controls were assayed for limb motor, anxiety, and vocal motor behaviors. A customized NanoString CodeSet, based on genetic work in later adulthood, was used to probe for the up regulation of genes involved in disease pathways and inflammation within the brainstem and vocal fold muscle. In summary, the data show sex- and genotype-differences in limb motor, anxiety, and vocal motor behaviors. Specifically, female Pink1−/− rats demonstrate less anxiety-like behavior compared to male Pink1−/− rats and female rats show increased locomotor activity compared to male rats. Pink1−/− rats also demonstrate prodromal ultrasonic vocalization dysfunction across all acoustic parameters and sex differences were present for intensity (loudness) and peak frequency. These data demonstrate a difference in phenotype in the Pink1−/− model. Tuba1c transcript level was identified as a key marker negatively correlated to ultrasonic vocalization at 2 months of age. Identifying genes, such as Tuba1c, may help determine early predictors of PD pathology in the Pink1−/− rat and serve as targets for future drug therapy studies.

Aging hastens locomotor decline in PINK1 knockout rats in association with decreased nigral, but not striatal, dopamine and tyrosine hydroxylase expression

“…al, 2022; Kelm-Nelson et al, 2021; Creed et. al, 2019; Villeneuve et al, 2016; Cai et al, 2019; Hoffmeister et al, 2020; Grant et al, 2015; Cullen et al, 2018; Lechner et al, 2022; Soto et al, 2024). Accordingly, this highlights the apparent complexities related to PINK1 function and its influence on nigrostriatal neurodegeneration and DA regulation (Urrutia, 2014).…”

Prodromal Parkinson disease signs are predicted by a whole-blood inflammatory transcriptional signature in young Pink1−/− rats

“…Rats communicate during social interactions by producing ultrasonic vocalizations (USVs) in part by contraction and adduction of the thyroarytenoid (TA) muscle [ 31 , 32 ]. At 2–3 months of age, in the prodromal period, Pink1 −/− rats show differences in acoustical parameters compared to wild-type rats [ 22 , 29 ]. Recent research has shown that loss of functional Pink1 in the TA muscle leads to increased inflammatory and cell death pathways including the TNF-α/NF-kB signaling pathway [ 28 ].…”

“…While previous cranial motor behavior and tissue-specific genetic studies have been done in the Pink1 −/− rat model, whole blood gene expression has not been evaluated [ 25 , 28 , 29 , 33 ]. By identifying whole blood gene expression profiles in early-stage PD, we can develop a transcriptomic signature capable of detecting PD in prodromal stages.…”

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

“…In early-adult (2 months of age) Pink1À/À rats, Tuba1c transcript level in the TA muscle was identified as a key gene negatively correlated to USV peak frequency providing a link to TA-specific gene expression and a potential role in vocalization. 45 However, no studies to date have comprehensively evaluated the female TA muscle gene expression. Here, we hypothesized that the expression of genes that regulate muscle contraction and mitochondrial function would be significantly dysregulated in the female Pink1À/À rat TA muscle compared with age-matched wild-type (WT) control rat TA muscle.…”

“…Independent of dopamine loss in both sexes, these behavioral differences within the same genetic model are worthy of studying. In early‐adult (2 months of age) Pink1 −/− rats, Tuba1c transcript level in the TA muscle was identified as a key gene negatively correlated to USV peak frequency providing a link to TA‐specific gene expression and a potential role in vocalization 45 . However, no studies to date have comprehensively evaluated the female TA muscle gene expression.…”