Research Article: Aging Reveals a Role for Nigral Tyrosine Hydroxylase ser31 Phosphorylation in Locomotor Activity Generation

Date Published: December 23, 2009

Publisher: Public Library of Science

Author(s): Michael F. Salvatore, Brandon S. Pruett, Sandy L. Spann, Charles Dempsey, Silvana Gaetani.

Abstract: Tyrosine hydroxylase (TH) regulates dopamine (DA) bioavailability. Its product, L-DOPA, is an established treatment for Parkinson’s disease (PD), suggesting that TH regulation influences locomotion. Site-specific phosphorylation of TH at ser31 and ser40 regulates activity. No direct evidence shows that ser40 phosphorylation is the dominating mechanism of regulating TH activity in vivo, and physiologically-relevant stimuli increase L-DOPA biosynthesis independent of ser40 phosphorylation. Significant loss of locomotor activity occurs in aging as in PD, despite less loss of striatal DA or TH in aging compared to the loss associated with symptomatic PD. However, in the substantia nigra (SN), there is equivalent loss of DA or TH in aging and at the onset of PD symptoms. Growth factors increase locomotor activity in both PD and aging models and increase DA bioavailability and ser31 TH phosphorylation in SN, suggesting that ser31 TH phosphorylation status in the SN, not striatum, regulates DA bioavailability necessary for locomotor activity.

Partial Text: We face an increased probability of reduced mobility (bradykinesia) with advancing age, with a 50% risk of this Parkinsonian-like symptom by age 85 [1], [2]. The neurobiological basis of this aging-related impairment to locomotion is crucial to resolve, particularly due to the imminent increase of the elderly population. Aging-related Parkinsonism presents symptoms similar to Parkinson’s disease (PD) and, like PD, they are progressive, impair performance of essential locomotor functions, and increase risk of cognitive impairment, dementia, and death [2]–[5]. Major dopamine (DA) loss of 70–80% in the striatum is thought to be required for major symptom presentation in PD [6]–[10]. However, in aged humans and animal models alike, striatal DA loss does not reach symptomatic levels seen in PD, ranging instead from 0 to 50% [11]–[15]. Throughout the lifespan there is also little if any aging-related loss of striatal tyrosine hydroxylase ((TH), the rate-limiting enzyme for DA biosynthesis) [15]–[20], which is in stark contrast to the 80% loss seen in symptomatic PD [6], [8]. Thus, it is curious why aging-related Parkinsonism occurs if DA and TH loss are not equivalent to the symptomatic levels seen in PD. If TH loss does not occur in striatum during aging, it is possible that either decreased striatal TH activity may contribute to Parkinsonism, or decreased TH protein or activity in another DA region is the source of Parkinsonism.

Somatodendritic release of nigral DA has been long established [34] and its pharmacological manipulation modulates locomotor-regulating functions of the basal ganglia and aspects of locomotion [39]–[41], [59]. Furthermore, transplantation of mouse fetal midbrain cells into the SN, rather than the striatum, of 6-OHDA-lesioned adult mice may have a greater restorative capacity to locomotor function [60]. Nonetheless, it has been questioned as to whether such manipulations could somehow coincidentally modulate striatal functions. Here we show, using intact and pharmacologically-naïve rats with inherent differences in locomotor activity, that locomotor activity generation capacities in an open-field correlate to nigral, but not striatal, DA tissue content. Furthermore, the aging-related loss of DA in the SN, rather than striatum, in conjunction with a significant decline in locomotor activity in the 30-month group supports a role for nigral DA tissue content in modulating locomotor activity generation. We note that movement speed was not correlated with nigral DA tissue content and was also not significantly different between the 12 and 30 month old subjects, suggesting this component of locomotor activity is not influenced by nigral DA content. Striatal and accumbal DA content do affect motivational aspects of locomotor activity [31]–[32], [61]. However, the lack of significant DA loss in striatum or nucleus accumbens between the age groups may have accounted for why there was not a significant correlation in these regions with locomotor speed.



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