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

Abstract

Mechanisms that augment dopamine (DA) signaling to compensate for tyrosine hydroxylase (TH) loss and delay motor impairment in Parkinsons 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 D1 receptor 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, D1 receptor expression increased only in lesioned SN. These results indicate that increased ser31 TH phosphorylation and D1 receptor in the SN, not striatum, augment DA signaling against TH loss to mitigate hypokinesia.

Differential expression of RET and GDNF family receptor, GFR-α1, between striatum and substantia nigra following nigrostriatal lesion: a case for diminished GDNF-signaling

“…The 6-OHDA lesion produced a time-dependent loss of TH+ neurons in the SN (Figure 1) (Kasanga et al, 2022). With >90% loss of TH protein confirmed in the striatum (93% by day 7 and 98% by day 28) after lesion induction (Fig.…”

“…As the temporal sequence of GDNF or BDNF receptor expression between striatum and SN during nigrostriatal neuron loss has not been established, we determined that expression of the ligands, GDNF and BDNF, were largely unaffected by nigrostriatal neuron loss, and, instead show that the GDNF receptors, GFR-α1 and RET, were differentially affected between striatum and SN over time after lesion induction. Of note, the samples used in this study were obtained from rats that had confirmed parkinsonian motor phenotypes, and significant loss of TH protein in both striatum (>95%) and SN (∼60%) by day 7 and even greater loss (>80%) in SN by day 28 (Kasanga et al, 2022). Notably, GDNF expression was minimally affected after lesion at both time points.…”

“…It may be argued that the timing of delivery in preclinical studies did not fully represent the severity of the disease stage in the clinical trials, wherein loss nigrostriatal neuron terminals was likely complete when GDNF was initiated ∼8 years post-diagnosis. The rats used in this study had greater than 95% TH and DA loss in striatum and beginning of nigrostriatal cell body loss and motor impairment (Kasanga et al, 2022), which gives a perspective on the possibility that the patients in clinical trials likely had very little, if any, available RET or GFR-α1. Few preclinical studies have investigated neuroprotection or restoration by targeting the GDNF receptors, but the available evidence suggests plausibility from such an approach to augment DA signaling by preserving TH protein expression in the SN (Kasanga et al, 2019; Pruett and Salvatore, 2013).…”

“…FAS revealed a significant reduction (≥75%) in contralateral forepaw use (to the lesioned hemisphere) as compared to the ipsilateral forepaw at day 7 in both the 7-day cohort (t=7.41, p <0.0001, df=8) and 28-day cohort (t=11.77, p <0.0001, df=8) with no significant difference between the two cohorts (data not shown). Rats with <25% contralateral forelimb use (6 out of 25) were excluded from further analysis (Kasanga et al, 2022).…”

“…Left panels, contralateralto lesion (CL); right panels; ipsilateral to lesion (L). Top panels, Day 7; bottom panels, Day 28 (Kasanga et al, 2022).…”