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

Abstract

AbstractMechanisms that augment dopamine (DA) signaling to compensate for tyrosine hydroxylase (TH) loss and delay motor impairment in Parkinson’s disease remain unidentified. The rat nigrostriatal pathway was unilaterally-lesioned by 6-OHDA to determine whether differences in DA content, TH protein, TH phosphorylation, or D1receptor expression in striatum or substantia nigra (SN) aligned with onset of hypokinesia at two time points. At 7 days, DA and TH loss in striatum exceeded 95%, whereas DA was unaffected in SN, despite ∼60% TH loss. At 28 days, hypokinesia was established. At both time points, ser31 TH phosphorylation increased only in SN, corresponding to less DA versus TH loss. ser40 TH phosphorylation was unaffected in striatum or SN. By day 28, D1receptor expression increased only in lesioned SN. These results indicate that increased ser31 TH phosphorylation and D1receptor in the SN, not striatum, augment DA signaling against TH loss to mitigate hypokinesia.Highlights–Despite >90% TH and DA loss in striatum, open-field locomotor activity did not decrease–Early after lesion, DA and TH loss in striatum exceeded 90%. In contrast, DA loss did not occur despite 60% TH loss in substantia nigra (SN).–TH loss was progressive in the SN, with loss also spreading contralateral to lesion.–Loss of TH protein in SN preceded cell loss ipsilateral and contralateral to lesion, indicating first stages of nigrostriatal neuron loss begin with loss of TH protein loss.–TH phosphorylation at ser31 in SN was associated with less, if any, DA loss compared to TH protein loss.–TH phosphorylation at ser40 did not change in either region and at any time during TH loss, suggesting no contribution to differences in DA loss against TH loss.–Expression of the D1 receptor increased 2.5-fold in the SN late, but not early, after lesion, suggesting a post-synaptic receptor response to offset DA loss in SN.–No increases in TH phosphorylation or D1 receptor expression in striatum at any time after lesion induction, indicating that compensatory mechanisms occur only in substantia nigra, but not in striatum, to delay onset of hypokinesia.