Parkinson's disease (PD) is a multifactorial neurodegenerative disease with aging as the leading risk factor (Gelders et al., 2018; Hall et al., 2018; Hindle, 2010; Collier et al., 2011; 2017). Nearly one million people in the USA are currently diagnosed with PD, and this number is rapidly rising alongside the aging population (De Lau and Breteler, 2006; Marras et al., 2018). Characterized by a loss of dopaminergic (DA) neurons from the substantia nigra (SN) and abnormal alpha-synuclein aggregation, PD manifests with symptoms such as bradykinesia, muscle rigidity, tremors, and gait impairments (Stefanis, 2012; Stoker and Greenland, 2018). Additional non-motor symptoms, such as early decline in executive functioning, stems from impaired norepinephrine (NE) and DA signaling in the prefrontal cortex (PFC) that can be observed in up to one-third of patients (Aarsland et al., 2017; Braak et al., 2003; Postuma and Berg, 2019; Nejtek et al., 2021; Durcan et al., 2019; Dirnberger and Jahanshahi, 2013; Salvatore et al., 2021). Notably, the motor symptoms of PD arise years into the disease course, and therefore patients are often pathologically well advanced prior to seeking medical attention, which hinders the ability to assess the earliest neurobiological processes of the disease (Berg et al., 2021; Postuma and Berg, 2019; Kordower et al., 2013; Hauser, 2018).

Rodent PD models may provide mechanistic insights into the stages of neuropathology that align with behavioral traits. However, while aging plays a crucial role in PD development, its neurobiological underpinnings are often overlooked and inadequately translated from animal models (Zeiss et al., 2017; Barker and Björklund, 2020). Moreover, whereas toxin models like 6-hydroxydopamine (6-OHDA) can induce nigrostriatal neuron loss of similar magnitude to that in human PD (Kasanga et al., 2023), they have been continuously criticized for the rapid nature of nigrostriatal neuron loss which does not emulate the rate of progressive loss occurring over years prior to motor symptom onset in human PD (Bezard et al., 2013; Dauer and Przedborski, 2003).

Unfortunately, efforts to mimic the human condition in rodent models with genetic or synuclein-based manipulation (Polinski, 2021) have yet to yield a reliable behavioral phenotype in concert with the hallmark changes of progressive loss of nigrostriatal neuron terminals and, to a lesser degree, cell body loss consistently seen in human PD (Kordower et al., 2013; Heng et al., 2023; Sun et al., 2013; Zhang et al., 2022).

PTEN-Induced Kinase 1 (PINK1) is a protein involved in mitophagy, with high expression in the SN of rodents and humans alike (Blackinton et al., 2007) and necessary for DA neuron survival (Wood-Kaczmar et al., 2008). Its function is compromised in one of the familial forms of PD, leading to early-onset PD with a median age of onset of 30–39 years old (Valente et al., 2004; Hatano et al., 2004; Ibáñez et al., 2006; Ricciardi et al., 2014; Borsche et al., 2020). Translating the phenotype of this mutation into in an animal model has been problematic. The PINK1 knockout (KO) mouse does not exhibit an early onset parkinsonian phenotype as hoped in developing this model, nor does it show loss of nigrostriatal neurons or dopamine (DA) (Kitada et al., 2007, Kitada et al., 2009). Instead, the PINK1 KO rat appears to emulate a slower onset and progression of motor impairment (Dave et al., 2014; Grant et al., 2015; Ferris et al., 2018; Grigoruţă et al., 2020). However, there is considerable inconsistency in the timing and severity of the onset of a parkinsonian motor phenotype. Bradykinesia can start at 4-months old and gradually worsen by 8-months of age (Dave et al., 2014). Grigoruţă et al. (2020) identified that motor decline occurred only with the addition of an environmental stressor. Meanwhile, De Haas et al. (2019) and Grant et al. (2015) report deficits only began at 8-months old. Given that PD also impairs cognitive function, studies using this rodent model have identified memory and learning impairments, and heightened anxiety, yet all at different ages (Pinizzotto et al., 2022; Maynard et al., 2020; Cai et al., 2019; Hoffmeister et al., 2022; Soto et al., 2024).

Importantly, the age of onset for humans with a PINK1 mutation is highly variable, ranging from 11- to 67-years of age, due to varying point mutations to large deletions (Bentivoglio et al., 2001; Kasten et al., 2018). Likewise, environmental factors and lifestyle may contribute to heterogeneity in the biological response to a PINK1 mutation (Cazeneuve et al., 2009; Taghavi et al., 2018; Steele et al., 2015), as suggested in the PINK1 KO rat examined by Grigoruţă et al. (2020). However, only one study has addressed whether aging may be a relevant factor in the inconsistent timing of motor phenotype onset against impaired DA signaling (Zhi et al., 2019). Thus far, only moderate loss, if any, of nigrostriatal neurons, DA, or tyrosine hydroxylase (TH) has ever been reported in this model (Dave et al., 2014; Villeneuve et al., 2016), and any DA loss is nowhere near the severity seen in human PD at diagnosis (Villeneuve et al., 2016; Dave et al., 2014; Creed et al., 2019, Creed et al., 2021; Zhi et al., 2019; Salvatore et al., 2022). Moreover, striatal DA or TH loss has not correlated with motor impairments (Dave et al., 2014; De Haas et al., 2019; Marquis et al., 2020). As such, we postulated that the impact of PINK1 mutation on locomotor function and DA signaling may be more comparable to human PD with advancing age.

To address if aging affects the nigrostriatal changes in TH and DA regulation in line with motor decline, we conducted a longitudinal study comparing male PINK1 KO and WT rats from 3-to 16-months old, and in another cohort, a cross-sectional study with both young adult (6–7-months) and aged (18–19-months) PINK1 KO and WT rats. We evaluated both motor and cognitive functioning, and tissue levels of DA, NE, and TH protein in the striatum, SN, and PFC. We predicted aging would reveal the motor phenotype and accompany decreases in catecholamine levels, akin to human PD progression. Our findings revealed frank hyperkinetic behavior coincident with elevated DA in the SN and striatum in young adult PINK1 KO rats. With aging, only nigral DA decreased by 18-months old in PINK1 KO rats, coinciding with decreased locomotor activity that was restricted to the PINK1 KO genotype. The hyperactive phenotype in young PINK1 KO is speculated to arise from compensatory mechanisms responding to compromised PINK1 function.