Abstract:In Parkinson disease (PD), a complex neurodegenerative disorder that affects nearly 10 million people worldwide, motor skills are significantly impaired. However, onset and progression of motor deficits and the neural correlates of these deficits are poorly understood. We used a genetic mouse model of PD (Pink1-/-), with phenotypic similarities to human PD, to investigate the manifestation of early-onset sensorimotor deficits. We hypothesized this mouse model would show early vocalization and gross motor dysfu… Show more
“…Consistent with our results, deficits in fine motor coordination were reported in one previous characterization of Parkin knockout mice generated by targeted deletion of exon 3 [ 17 ]; however, in another independently generated exon 3 deleted knockout model, no motor deficits were reported although these mice exhibited learning and memory deficits [ 28 ]. More recently, similar fine motor deficits were found in Pink1 knockout mice in the absence of nigrostriatal degenerative pathology [ 29 ], further underscoring the importance of performing more sensitive behavioural testing in mouse models of PD. In our study, we were unable to determine the age-of-onset of the motor deficits, although it was reported that Pink1 knockout mice take approximately six months to exhibit detectable locomotor dysfunction [ 29 ].…”
Section: Resultsmentioning
confidence: 79%
“…More recently, similar fine motor deficits were found in Pink1 knockout mice in the absence of nigrostriatal degenerative pathology [ 29 ], further underscoring the importance of performing more sensitive behavioural testing in mouse models of PD. In our study, we were unable to determine the age-of-onset of the motor deficits, although it was reported that Pink1 knockout mice take approximately six months to exhibit detectable locomotor dysfunction [ 29 ]. Figure 3.…”
Mutations in PINK1 and Parkin result in autosomal recessive Parkinson's disease (PD). Cell culture and in vitro studies have elaborated the PINK1-dependent regulation of Parkin and defined how this dyad orchestrates the elimination of damaged mitochondria via mitophagy. PINK1 phosphorylates ubiquitin at serine 65 (Ser65) and Parkin at an equivalent Ser65 residue located within its N-terminal ubiquitin-like domain, resulting in activation; however, the physiological significance of Parkin Ser65 phosphorylation in vivo in mammals remains unknown. To address this, we generated a Parkin Ser65Ala (S65A) knock-in mouse model. We observe endogenous Parkin Ser65 phosphorylation and activation in mature primary neurons following mitochondrial depolarization and reveal this is disrupted in ParkinS65A/S65A neurons. Phenotypically, ParkinS65A/S65A mice exhibit selective motor dysfunction in the absence of any overt neurodegeneration or alterations in nigrostriatal mitophagy. The clinical relevance of our findings is substantiated by the discovery of homozygous PARKIN (PARK2) p.S65N mutations in two unrelated patients with PD. Moreover, biochemical and structural analysis demonstrates that the ParkinS65N/S65N mutant is pathogenic and cannot be activated by PINK1. Our findings highlight the central role of Parkin Ser65 phosphorylation in health and disease.
“…Consistent with our results, deficits in fine motor coordination were reported in one previous characterization of Parkin knockout mice generated by targeted deletion of exon 3 [ 17 ]; however, in another independently generated exon 3 deleted knockout model, no motor deficits were reported although these mice exhibited learning and memory deficits [ 28 ]. More recently, similar fine motor deficits were found in Pink1 knockout mice in the absence of nigrostriatal degenerative pathology [ 29 ], further underscoring the importance of performing more sensitive behavioural testing in mouse models of PD. In our study, we were unable to determine the age-of-onset of the motor deficits, although it was reported that Pink1 knockout mice take approximately six months to exhibit detectable locomotor dysfunction [ 29 ].…”
Section: Resultsmentioning
confidence: 79%
“…More recently, similar fine motor deficits were found in Pink1 knockout mice in the absence of nigrostriatal degenerative pathology [ 29 ], further underscoring the importance of performing more sensitive behavioural testing in mouse models of PD. In our study, we were unable to determine the age-of-onset of the motor deficits, although it was reported that Pink1 knockout mice take approximately six months to exhibit detectable locomotor dysfunction [ 29 ]. Figure 3.…”
Mutations in PINK1 and Parkin result in autosomal recessive Parkinson's disease (PD). Cell culture and in vitro studies have elaborated the PINK1-dependent regulation of Parkin and defined how this dyad orchestrates the elimination of damaged mitochondria via mitophagy. PINK1 phosphorylates ubiquitin at serine 65 (Ser65) and Parkin at an equivalent Ser65 residue located within its N-terminal ubiquitin-like domain, resulting in activation; however, the physiological significance of Parkin Ser65 phosphorylation in vivo in mammals remains unknown. To address this, we generated a Parkin Ser65Ala (S65A) knock-in mouse model. We observe endogenous Parkin Ser65 phosphorylation and activation in mature primary neurons following mitochondrial depolarization and reveal this is disrupted in ParkinS65A/S65A neurons. Phenotypically, ParkinS65A/S65A mice exhibit selective motor dysfunction in the absence of any overt neurodegeneration or alterations in nigrostriatal mitophagy. The clinical relevance of our findings is substantiated by the discovery of homozygous PARKIN (PARK2) p.S65N mutations in two unrelated patients with PD. Moreover, biochemical and structural analysis demonstrates that the ParkinS65N/S65N mutant is pathogenic and cannot be activated by PINK1. Our findings highlight the central role of Parkin Ser65 phosphorylation in health and disease.
“…We tested the specific hypotheses that Pink−/− female rats would demonstrate impaired limb motor and vocal performance with increased anxiety and anhedonia, and that changes which would become more pronounced with disease progression. The statistical analysis was designed to account for body weight; Pink1−/−rats are consistently heavier compared to controls [30,31]. Finally, estrous phase appeared to be an important variable for the number of calls produced within a testing session, but did not interact with other limb motor, acoustic, anhedonia, or anxiety behaviors.…”
Section: Discussionmentioning
confidence: 99%
“…The Pink1−/− rat model replicates the progression of PD through both preclinical and mid-symptomatic phases, displaying characteristic features such as early-onset, slow progression of sensorimotor deficits, and brainstem neuropathology [28]. Previous research has extensively assayed this model for limb motor deficits as well as ultrasonic vocalization and swallowing deficits [29][30][31][32][33][34][35]. An additional consideration in the Pink1−/− rat model is the acknowledgement of sex-differences in research designs and the resulting potential sex-biased results, as primary research using the Pink1−/− rat model has been done exclusively in males.…”
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.
“…Using the high‐frequency‐modulated call results, baseline and 1 WPS were chosen for additional in depth analysis as follows: a trained reviewer independently classified and quantified all calls in a blinded fashion within the first 90 s after the first detected call. Ten call types (i.e., constant, downsweep, upsweep, harmonic, multiple jumps, jump up, jump down, half cycle, full cycle, and two cycle) were identified and grouped accordingly into four call categories based on complexity: simple, complex, jump, and cycle (Figure ) (Grant et al, ; Kelm‐Nelson et al, ). The following acoustic properties that are common in communication signals among various species, including mice and humans, were measured for each call type and category (Basken, Connor, & Ciucci, ): percentage of call type (%), bandwidth (kHz), peak frequency (kHz), duration (ms), and duration of peak frequency (ms).…”
The recurrent laryngeal nerve (RLN) is responsible for normal vocal‐fold (VF) movement, and is at risk for iatrogenic injury during anterior neck surgical procedures in human patients. Injury, resulting in VF paralysis, may contribute to subsequent swallowing, voice, and respiratory dysfunction. Unfortunately, treatment for RLN injury does little to restore physiologic function of the VFs. Thus, we sought to create a mouse model with translational functional outcomes to further investigate RLN regeneration and potential therapeutic interventions. To do so, we performed ventral neck surgery in 21 C57BL/6J male mice, divided into two groups: Unilateral RLN Transection (n = 11) and Sham Injury (n = 10). Mice underwent behavioral assays to determine upper airway function at multiple time points prior to and following surgery. Transoral endoscopy, videofluoroscopy, ultrasonic vocalizations, and whole‐body plethysmography were used to assess VF motion, swallow function, vocal function, and respiratory function, respectively. Affected outcome metrics, such as VF motion correlation, intervocalization interval, and peak inspiratory flow were identified to increase the translational potential of this model. Additionally, immunohistochemistry was used to investigate neuronal cell death in the nucleus ambiguus. Results revealed that RLN transection created ipsilateral VF paralysis that did not recover by 13 weeks postsurgery. Furthermore, there was evidence of significant vocal and respiratory dysfunction in the RLN transection group, but not the sham injury group. No significant differences in swallow function or neuronal cell death were found between the two groups. In conclusion, our mouse model of RLN injury provides several novel functional outcome measures to increase the translational potential of findings in preclinical animal studies. We will use this model and behavioral assays to assess various treatment options in future studies.
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