Atp13a2 expression in the periaqueductal gray is decreased in the Pink1 -/- rat model of Parkinson disease

Abstract

Vocal communication deficits are common in Parkinson disease (PD). Widespread alpha-synuclein pathology is a common link between familial and sporadic PD, and recent genetic rat models based on familial genetic links increase the opportunity to explore vocalization deficits and their associated neuropathologies. Specifically, the Pink1 knockout (−/−) rat presents with early, progressive motor deficits, including significant vocal deficits, at 8 months of age. Moreover, this rat model exhibits alpha-synuclein pathology compared to age-matched non-affected wildtype (WT) controls. Aggregations are specifically dense within the periaqueductal gray (PAG), a brainstem region involved in the coordination of emotional and volitional control of vocalizations. Here, we investigated changes in gene expression within the PAG at 8 months of age in Pink1 −/− rats compared to WT. Our data demonstrate that Pink1 −/− rat mRNA expression levels of alpha-synuclein are comparable to WT. However, Pink1 −/− rats show significantly decreased levels of Atp13a2, a transmembrane lysosomal P5-type ATPase suggesting a potential mechanism for the observed abnormal aggregation. We found no difference in the expression of glucocerebrosidase (Gba) or the CASP8 and FADD-like apoptosis regulator (Cflar). Further, we show that mRNA expression levels of dopaminergic markers including Th, D1 and D2 receptor as well as GABA signaling markers including Gaba-A and glutamate decarboxylase 2 (Gad2) do not differ between genotypes. However, we found that glutamate decarboxylase 1 (Gad1) is significantly reduced in this PD model suggesting possible disruption of neurotransmission within the PAG. These results are the first to suggest the hypothesis that alpha-synuclein aggregation in this model is not a result of increased transcription, but rather a deficit in the breakdown and clearance, and that the observed vocal deficits may be related to impaired neural transmission. Altogether, these findings are consistent with the hypothesis that differences in neural substrate sensitivity contribute to the early pathogenesis of vocalizations and motivation to communicate in the Pink1 −/− rat model of PD. Our results suggest novel therapeutic pathways, including the lysosomal degradation pathway, which can be used in to further study the pathogenesis and treatment of vocal dysfunction PD.

Pink1 −/− Rats Show Early-Onset Swallowing Deficits and Correlative Brainstem Pathology

“…In addition to reductions in TH-ir, previous data have revealed evidence of additional pathology outside of the nigrostriatal dopamine system in Pink1 −/− rats at 8 months of age [27, 29]. Specifically, there is evidence of alpha-synuclein aggregation in the nucleus ambiguus and periaqueductal gray [27, 29], which may also contribute to the preclinical manifestation of cranial sensorimotor deficits.…”

“…Specifically, there is evidence of alpha-synuclein aggregation in the nucleus ambiguus and periaqueductal gray [27, 29], which may also contribute to the preclinical manifestation of cranial sensorimotor deficits. Here, we show quantified evidence of increased alpha-synuclein protein concentrations in the nucleus ambiguus of Pink1 −/− rats, compared to WT.…”

“…While it is clear that nigrostriatal dopamine does play a role in regulating muscle movements for swallowing, there are clearly other mechanisms associated with certain swallowing deficits, especially in the early stages of PD. Specifically, we show a significant decrease in mastication rate in the Pink1 −/− model between 4 and 8 month of age; this corresponds to the increased presence of alpha-synuclein aggregation in brainstem regions, including the nucleus ambiguus, important for vocalization and swallowing behaviors [27, 29]. However, while the inter- and intra-rater reliability measures were very high, a significant limitation of this work is the capture rate (30 frames/s) and resolution of the video used for analysis [51].…”

“…Pink1 −/− rats have been used to study early behavioral deficits [27, 28]. Specifically, Pink1 −/− rats develop sensorimotor deficits, including progressive vocalization and oromotor (tongue, chewing) deficits [27], as well as observable alpha-synuclein aggregations in brainstem regions (the periaqueductal gray and nucleus ambiguus) important in oromotor behaviors [27, 29]. However, oropharyngeal swallow function has not been evaluated in this model of PD.…”

Data in support of qPCR primer design and verification in a Pink1 −/− rat model of Parkinson disease

“…Additionally, results of Sanger sequencing of qPCR reaction products (FASTA aligned sequences) are presented for genes of interest. Results and further interpretation and discussion can be found in the original research article “Atp13a2 expression in the periaqueductal gray is decreased in the Pink1 −/− rat model of Parkinson disease” [1] .…”