Early-onset Parkinsonian behaviors in female Pink1-/- rats

Abstract

Parkinson disease (PD) is a progressive, neurological disease that affects millions of individuals worldwide. Although instability, rigidity, tremor, and bradykinesia are considered hallmark motor signs of the disease, these are not apparent until mid-to-late stage. In addition to limb motor impairment, individuals with PD also exhibit early-onset speech dysfunction and reduced vocal intelligibility as well as anhedonia and anxiety. Many of these clinical signs vary according to sex in humans with PD. In this study, a translational genetic rat model of early-onset PD (Pink1−/−) was used to address significant gaps in knowledge concerning sex-specific characteristics of limb sensorimotor deficits, vocal motor dysfunction, and changes in affective state. Traditional behavioral tests of limb function, ultrasonic vocalization, anxiety, and anhedonia in the Pink1−/− female rat and wildtype controls were used to test the hypothesis that behavioral performance would significantly differ between genotypes, and that these differences would increase with disease progression (age of the rat). Results demonstrate that Pink1−/− female rats do not exhibit limb sensorimotor deficits but do have significantly reduced intensity (loudness) of vocalizations, and present with anhedonia and anxiety by 8 months of age. Consistent with an early-disease model, Pink1−/− female rats do not exhibit significant decreases in nigrostriatal catecholamines/ metabolites, as measured by HPLC. These results are significant in expanding knowledge of earlyonset deficits in the female Pink1−/− genetic rat model of PD.

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

“…Previously recorded female vocalization data [ 26 ] from WT and Pink1 −/− rats was used in a WGCNA to identify vocalization-associated modules (Fig. 4 ).…”

“…Phenotypically, motor signs of PD manifest differently in males compared to female Pink1 −/− rats [ 26 ]. For example, females do not show the classical limb motor deficits in tapered balance beam or cylinder tests compared to progressive slowness and increased number of errors in males.…”

“…A study of female-specific behavior was initially published in Marquis et al, 2019 [ 26 ]. Methods for data collection have been previously described [ 24 , 58 , 66 ].…”

“…The Pink1 −/− rat, related to the PARK6 phenotype of human familial PD, demonstrates early motor deficits including changes to ultrasonic vocal production [ 24 , 25 ]. Specifically, data show that male and female Pink1 −/− rats exhibit early (2 months of age) ultrasonic vocalization changes to intensity (loudness) compared to non-affected wildtype (WT) control rats [ 24 , 26 ]. Additional acoustic deficits include changes to frequency range in male rats at 8 months of age [ 24 ].…”

Psychological distress and lack of PINK1 promote bioenergetics alterations in peripheral blood mononuclear cells

“…In addition, mitophagy is regulated via other pathways including the serine/threonine kinase AKT pathway 20 . As in PD patients, PINK1 knockouts (PINK1-KO) rats faithfully manifest progressive motor and non-motor symptoms 21,22 , significant loss of dopaminergic neurons in the substantia nigra (SN) 22,23 , mitochondrial deficiency [24][25][26][27] and alterations of antioxidant proteins 25 in the brain starting at two months of age 3 . In contrast to other cell types, neurons are highly vulnerable to neurodegeneration in response to PINK1 deficiency.…”