Modulation of nigral dopamine signaling mitigates parkinsonian signs of aging: evidence from intervention with calorie restriction or inhibition of dopamine uptake

Nigral-specific increase in ser31 tyrosine hydroxylase phosphorylation offsets dopamine loss and forestalls hypokinesia onset during progressive nigrostriatal neuron loss

“…Our study showed that despite virtually complete loss of striatal DA or TH by 7 days, hypokinesia onset was not uniform, and was not decreased overall in two cohorts. Despite the knowledge that DA release in the SN has been established for nearly 50 years [51], consideration of nigral DA signaling in parkinsonian sign onset and severity is largely neglected and therefore sparsely investigated [9,[27][28][29]37,[52][53][54][55]. Our systematic and contemporaneous comparison of lesion-induced changes in DA signaling components in striatum and SN revealed the respective roles of DA regulation against the timing of hypokinesia onset.…”

“…Tyrosine hydroxylase protein was quantified against a calibrated standard traceable over multiple studies [9,31,[44][45][46][47]. Optimal total protein load for TH determination in striatum and SN was 4 and 8 µg, respectively, using the primary antibody obtained from Millipore (Temecula, CA, cat #AB152).…”

“…Nevertheless, the possibility that nigral DA signaling affects locomotor function is rarely considered, and instead, remaining TH+ cells are quantified as a static biomarker of neuron viability. Yet, multiple lines of evidence challenge the perspective that deficiencies in striatal DA signaling are the chief regulating mechanism of parkinsonian sign onset or severity [7,9,14,18,19,[21][22][23][24][25][26][27]. Moreover, local modulation of nigral DA signaling affect locomotor activity levels autonomously from any change in striatal DA [9,28,29].…”

“…Yet, multiple lines of evidence challenge the perspective that deficiencies in striatal DA signaling are the chief regulating mechanism of parkinsonian sign onset or severity [7,9,14,18,19,[21][22][23][24][25][26][27]. Moreover, local modulation of nigral DA signaling affect locomotor activity levels autonomously from any change in striatal DA [9,28,29].…”

“…Changes in TH phosphorylation stoichiometry at ser31 or ser40 during lesion progression were evaluated against of DA vs TH loss as a compensatory mechanism, as suggested by changes in striatal TH activity or phosphorylation in PD models [30][31][32][33][34] and human PD [35]. Finally, as DA D 1 agonists can mitigate parkinsonism [36], and their function in the SN affects basal ganglia function and locomotor activity [9,29,[37][38][39], we also evaluated if expression of the DA D1 receptor [40][41][42][43] changed in response to DA loss. Our results clearly indicate increased TH phosphorylation at ser31 offsets TH protein or cell loss to maintain DA levels only in the SN, and temporally coincided with forestalling hypokinesia.…”