title: 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.
authors.affiliation: Department of Surgery, Division of Otolaryngology, University of Wisconsin-Madison, Madison, WI, USA. Electronic address: CAKelm@wisc.edu.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Kelm-Nelson
authors.affiliation: Department of Zoology, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Stevenson
authors.affiliation: Department of Surgery, Division of Otolaryngology, University of Wisconsin-Madison, Madison, WI, USA; Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA; Department of Communication Sciences and Disorders, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Ciucci
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D055786:Gene Knockout Techniques; D005962:Glucosylceramidase / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D010487:Periaqueductal Gray / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics*; D006180:Proton-Translocating ATPases / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D015415:Biomarkers; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D005962:Glucosylceramidase; D005968:Glutamate Decarboxylase; D011494:Protein Kinases; D006180:Proton-Translocating ATPases; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011963:Receptors, GABA-A; D014446:Tyrosine 3-Monooxygenase; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase; C000620613:Atp13a2 protein, rat; C000614251:CFLAR protein, rat; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2
keywords: Alpha synuclein; Atp13a2; Gad1; Parkinson disease; Periaqueductal gray; Pink1; Rat; Ultrasonic vocalization