Evidence of Neurobiological Changes in the Presymptomatic PINK1 Knockout Rat

Ferris, Craig F.; Morrison, Thomas R.; Iriah, Sade; Malmberg, Samantha; Kulkarni, Praveen; Hartner, Jochen C.; Trivedi, Malav Suchin

doi:10.3233/jpd-171273

Cited by 26 publications

(26 citation statements)

References 97 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In either case, it has been proposed that altered coupling between glutamatergic and dopaminergic firing at nigrostriatal synapses could play a role in PD-related neurodegeneration via over-activation of glutamate receptors or metabolic stress (Calabresi et al, 1997). A recent imaging and biochemical analysis of PINK1 KO rats revealed altered glutathione and ATP in various brain regions including striatum, suggesting that our observation of multiple neurotransmitter alterations in PINK1 KO rats at baseline (Figure 1A–C) and upon high potassium stimulation (Figure 2A–C, E) are part of a broader set of neurobiological abnormalities resulting from PINK1 deficiency (Ferris et al, 2018).…”

Section: Discussionmentioning

confidence: 66%

Basal and Evoked Neurotransmitter Levels in Parkin, DJ-1, PINK1 and LRRK2 Knockout Rat Striatum

Creed

Menalled²,

Casey³

et al. 2019

Neuroscience

View full text Add to dashboard Cite

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and is characterized by the loss of neurons in the substantia nigra that project to the striatum and release dopamine (DA), which is required for normal movement. Common non-motor symptoms likely involve abnormalities with other neurotransmitters, such as serotonin, norepinephrine, acetylcholine, glycine, glutamate and gamma-aminobutyric acid (GABA). As part of a broad effort to provide better PD research tools, the Michael J. Fox Foundation for Parkinson’s Research funded the generation and characterization of knockout (KO) rats for genes with PD-linked mutations, including PINK1, Parkin, DJ-1 and LRRK2. Here we extend the phenotypic characterization of these lines of KO rats to include in vivo microdialysis to measure both basal and potassium-induced release of the above neurotransmitters and their metabolites in the striatum of awake and freely moving rats at ages 4, 8 and 12 months compared to wild-type (WT) rats. We found age-dependent abnormalities in basal DA, glutamate and acetylcholine in PINK1 KO rats and age-dependent abnormalities in basal DA metabolites in Parkin and LRRK2 KO rats. Parkin KO rats had increased glycine release while DJ-1 KO rats had decreased glutamate release and increased acetylcholine release compared to WT rats. All lines except DJ-1 KO rats showed age-dependent changes in release of one or more neurotransmitters. Our data suggest these rats may be useful for studies of PD-related synaptic dysfunction and neurotransmitter dynamics as well as studies of the normal and pathogenic functions of these genes with PD-linked mutations.

show abstract

Section: Discussionmentioning

confidence: 66%

Basal and Evoked Neurotransmitter Levels in Parkin, DJ-1, PINK1 and LRRK2 Knockout Rat Striatum

Creed

Menalled²,

Casey³

et al. 2019

Neuroscience

View full text Add to dashboard Cite

show abstract

“…Activation of this pathway results in selective autophagy. Thus, loss of function mutations in this process ultimately lead to increases in oxidative buildup and mitochondrial damage which has been previously reported [42,[45][46][47][48].…”

Section: Discussionmentioning

confidence: 70%

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

Kelm‐Nelson

Gammie

2020

BMC Genomics

View full text Add to dashboard Cite

Background Parkinson’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. Results Knockout 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. Conclusions Overall, 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.

show abstract

“…This was described as a possible functional presynaptic compensatory effect by a yet unknown mechanism. A recent imaging study hypothesized that a reorganization of the anatomical connectivity in the brain occurs to compensate for the loss of DA neurons in the SNpc (Cai et al , 2019; Ferris et al , 2018). In this study, we investigated the reproducibility of the Pink1 −/− rat model by evaluating behavioural dysfunction, loss of DA neurons in the SNpc and extracellular striatal dopamine concentrations in 8-month-old Pink1 −/− male rats.…”

Section: Introductionmentioning

confidence: 99%

To be or not to be pink(1): contradictory findings in an animal model for Parkinson’s disease

Haas

Heltzel

Tax

et al. 2019

Brain Communications

View full text Add to dashboard Cite

The PTEN-induced putative kinase 1 knockout rat (Pink1−/−) is marketed as an established model for Parkinson’s disease, characterized by development of motor deficits and progressive degeneration of half the dopaminergic neurons in the substantia nigra pars compacta by 8 months of age. In this study, we address our concerns about the reproducibility of the Pink1−/− rat model. We evaluated behavioural function, number of substantia nigra dopaminergic neurons and extracellular striatal dopamine concentrations by in vivo microdialysis. Strikingly, we and others failed to observe any loss of dopaminergic neurons in 8-month-old male Pink1−/− rats. To understand this variability, we compared key experimental parameters from the different studies and provide explanations for contradictory findings. Although Pink1−/− rats developed behavioural deficits, these could not be attributed to nigrostriatal degeneration as there was no loss of dopaminergic neurons in the substantia nigra and no changes in neurotransmitter levels in the striatum. To maximize the benefit of Parkinson’s disease research and limit the unnecessary use of laboratory animals, it is essential that the research community is aware of the limits of this animal model. Additional research is needed to identify reasons for inconsistency between Pink1−/− rat colonies and why degeneration in the substantia nigra is not consistent.

show abstract

Evidence of Neurobiological Changes in the Presymptomatic PINK1 Knockout Rat

Abstract: These data reveal early markers, and highlight novel brain regions involved in the pathology of PD in the PINK1 -/- rat before behavioral dysfunction occurs.

Cited by 26 publications

References 97 publications

Basal and Evoked Neurotransmitter Levels in Parkin, DJ-1, PINK1 and LRRK2 Knockout Rat Striatum

Basal and Evoked Neurotransmitter Levels in Parkin, DJ-1, PINK1 and LRRK2 Knockout Rat Striatum

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

To be or not to be pink(1): contradictory findings in an animal model for Parkinson’s disease

Contact Info

Product

Resources

About