Nigral-specific increase in ser31 phosphorylation compensates for tyrosine hydroxylase protein and nigrostriatal neuron loss: Implications for delaying parkinsonian signs

Kasanga, Ella A.; Han, Yoonhee; Shifflet, Marla K.; Navarrete, Walter; McManus, Robert; Parry, Caleb; Barahona, Arturo; Nejtek, Vicki A.; Manfredsson, Fredric P.; Kordower, Jeffrey H.; Richardson, Jason R.; Salvatore, Michael F.

doi:10.1016/j.expneurol.2023.114509

Cited by 10 publications

(37 citation statements)

References 101 publications

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“…Overall, the motor findings in this study, along with our previous results using this model (Salvatore et al, 2022) indicate that young adult PINK1 KO rats possibly undergo a compensatory phase of heightened activity before evident motor decline (Kasanga et al, 2023). This hyperactivity of young Pink1 KO rats has only been reported twice in previous studies (Ferris et al, 2018; Salvatore et al, 2022), but has yet to be reported in human PD, suggesting that the rat species may respond differently to a PINK1 mutation than humans.…”

Section: Discussionsupporting

confidence: 79%

“…Tissue was sonicated in perchloric acid/EDTA solution and spun to precipitate the protein pellet for further processing for quantitative blot immunolabeling of TH protein (Salvatore et al, 2012). The supernatant was then processed for analysis of dopamine (DA), norepinephrine (NE), and dihydroxyphenylacetic acid (DOPAC) using high-performance liquid chromatography (HPLC, for details on procedure, see Kasanga et al, 2023). The recovered protein pellet was further processed for western blot-based analysis and quantitation of TH protein (Millipore, Temecula, cat #: AB152; 1:1000 dil, CA, USA) against a calibrated TH protein standard to determine ng TH per µg total protein (Kasanga et al, 2023)…”

Section: Methodsmentioning

confidence: 99%

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Aging hastens locomotor decline in PINK1 knockout rats in association with decreased nigral, but not striatal, dopamine and tyrosine hydroxylase expression

Soto,

McManus,

Navarrete-Barahona

et al. 2024

Preprint

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Parkinsons disease (PD) rodent models provide insight into the relationship between nigrostriatal dopamine (DA) signaling and locomotor function. Although toxin-based rat models produce frank nigrostriatal neuron loss and eventual motor decline characteristic of PD, the rapid nature of neuronal loss may not adequately translate premotor traits, such as cognitive decline. Unfortunately, rodent genetic PD models, like the Pink1 knockout (KO) rat, often fail to replicate the differential severity of striatal DA and tyrosine hydroxylase (TH) loss, and a bradykinetic phenotype, reminiscent of human PD. To elucidate this inconsistency, we evaluated aging as a progression factor in the timing of motor and non-motor cognitive impairments. Male PINK1 KO and age-matched wild type (WT) rats were evaluated in a longitudinal study from 3 to 16 months old in one cohort, and in a cross-sectional study of young adult (6-7 months) and aged (18-19 months) in another cohort. Young adult PINK1 KO rats exhibited hyperkinetic behavior associated with elevated DA and TH in the substantia nigra (SN), which decreased therein, but not striatum, in the aged KO rats. Additionally, norepinephrine levels decreased in aged KO rats in the prefrontal cortex (PFC), paired with a higher DA content in young and aged KO. Although a younger age of onset characterizes familial forms of PD, our results underscore the critical need to consider age-related factors. Moreover, the results indicate that compensatory mechanisms may exist to preserve locomotor function, evidenced by increased DA in the SN early in the lifespan, in response to deficient PINK1 function, which declines with aging and the onset of motor impairment.

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Section: Discussionsupporting

confidence: 79%

Section: Methodsmentioning

confidence: 99%

Aging hastens locomotor decline in PINK1 knockout rats in association with decreased nigral, but not striatal, dopamine and tyrosine hydroxylase expression

Soto,

McManus,

Navarrete-Barahona

et al. 2024

Preprint

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“…Notably, these outcomes contrast with reports from other studies, where the timing of initial motor deficits and the extent of DA loss in this model range widely, with some indicating no deficits and others observing deficits emerging between 4 and 8 months ( Dave et al, 2014 ; Grant et al, 2015 ; de Haas et al, 2019 ; Salvatore et al, 2022 ; Soto et al, 2024 ). This period of observed hyperkinesia may be attributed to a compensatory phase preceding symptomatic DA loss, potentially reflecting the premotor phase of PD ( Blesa et al, 2017 ; Creed et al, 2021 ; Kasanga et al, 2023 ; Soto et al, 2024 ). While other types of motor tests in rats may reveal specific deficits, such as in gait, the OFT used here assesses both spontaneous movement and speed, two motor aspects critical to maze completion.…”

Section: Discussionmentioning

confidence: 99%

PINK1 knockout rats show premotor cognitive deficits measured through a complex maze

Soto,

Nejtek,

Siderovski

et al. 2024

Front. Neurosci.

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Cognitive decline in Parkinson’s disease (PD) is a critical premotor sign that may occur in approximately 40% of PD patients up to 10 years prior to clinical recognition and diagnosis. Delineating the mechanisms and specific behavioral signs of cognitive decline associated with PD prior to motor impairment is a critical unmet need. Rodent PD models that have an impairment in a cognitive phenotype for a time period sufficiently long enough prior to motor decline can be useful to establish viable candidate mechanisms. Arguably, the methods used to evaluate cognitive decline in rodent models should emulate methods used in the assessment of humans to optimize translation. Premotor cognitive decline in human PD can potentially be examined in the genetically altered PINK1−/− rat model, which exhibits a protracted onset of motor decline in most studies. To increase translation to cognitive assessment in human PD, we used a modified non-water multiple T-maze, which assesses attention, cognitive flexibility, and working memory similarly to the Trail Making Test (TMT) in humans. Similar to the deficiencies revealed in TMT test outcomes in human PD, 4-month-old PINK1−/− rats made more errors and took longer to complete the maze, despite a hyperkinetic phenotype, compared to wild-type rats. Thus, we have identified a potential methodological tool with cross-species translation to evaluate executive functioning in an established PD rat model.

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“…The increased travel distances and velocities post-SAL treatment suggest a potential reversal of bradykinesia, a cardinal symptom of PD, which aligns with previous research emphasizing the importance of restoring dopaminergic transmission to alleviate PD-associated motor deficits as well as highlighting the motor-enhancing effects of various neuroprotective agents in PD models [ 30 , 37 ]. In addition, TH, a rate-limiting enzyme in dopamine synthesis, typically shows decreased expression in PD [ 38 ], serving as a marker for the loss of dopaminergic neurons. In parallel, we observed that elevated levels of α-synuclein, a protein implicated in PD pathogenesis due to its tendency to form toxic aggregates [ 39 ], were significantly reduced following SAL treatment.…”

Section: Discussionmentioning

confidence: 99%

Salidroside Mediated the Nrf2/GPX4 Pathway to Attenuates Ferroptosis in Parkinson’s Disease

Shen,

Chen,

et al. 2024

Neurochem Res

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Parkinson’s Disease (PD) is characterized by the loss of dopaminergic neurons, with ferroptosis playing a significant role. Salidroside (SAL) has shown neuroprotective potential, this study aims to explore its capacity to mitigate ferroptosis in PD, focusing on the modulation of the Nuclear Factor E2-Related Factor 2 (Nrf2)/ Glutathione Peroxidase 4 (GPX4) pathway. Male C57BL/6 mice were subjected to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD-like symptoms, followed by SAL and Nrf2 inhibitor administration. Then behavioral tests, immunohistochemical staining, transmission electron microscopy, and Western blot analysis were conducted to assess motor functions, pathological changes, ferroptosis, and related protein expressions. In vitro, SH-SY5Y cells were treated with erastin to induce ferroptosis to assess the protective effects of SAL. Additionally, A53T-α-synuclein (α-syn) was used to stimulate the PD model, SAL and a Nrf2 inhibitor (ML385) was utilized to elucidate the role of the Nrf2/GPX4 pathway in mitigating ferroptosis in PD. In vivo, SAL significantly improved motor functions and reduced the expression of α-syn, while increasing tyrosine hydroxylase (TH) expression of PD mice. Additionally, SAL treatment notably enhanced the levels of antioxidants and reduced MDA and iron content in the substantia nigra of PD mice. In vitro, SAL treatment increased the TH, GPX4, Nrf2 expression, and mitochondrial membrane potential whereas alleviated ferroptosis through the Nrf2/GPX4 pathway, as evidenced in erastin-induced and α-syn overexpressing SH-SY5Y cells. While these effects were reversed upon Nrf2 inhibition. SAL demonstrates significant potential in mitigating PD pathology and ferroptosis, positioning the Nrf2/GPX4 pathway as a promising therapeutic target. However, future studies should focus on the long-term effects of SAL, its pharmacokinetics, addressing the multifactorial nature of PD pathogenesis.

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Nigral-specific increase in ser31 phosphorylation compensates for tyrosine hydroxylase protein and nigrostriatal neuron loss: Implications for delaying parkinsonian signs

Cited by 10 publications

References 101 publications

Aging hastens locomotor decline in PINK1 knockout rats in association with decreased nigral, but not striatal, dopamine and tyrosine hydroxylase expression

Aging hastens locomotor decline in PINK1 knockout rats in association with decreased nigral, but not striatal, dopamine and tyrosine hydroxylase expression

PINK1 knockout rats show premotor cognitive deficits measured through a complex maze

Salidroside Mediated the Nrf2/GPX4 Pathway to Attenuates Ferroptosis in Parkinson’s Disease

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