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Kasanga, E.

Publications and source records attributed to Kasanga, E..

2 recordsLinked to original sources
bioRxiv2023

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

Although glial cell line-derived neurotrophic factor (GDNF) showed efficacy in preclinical and early clinical studies to alleviate parkinsonian signs in Parkinsons disease (PD), later trials did not meet primary endpoints, giving pause to consider further investigation. While GDNF dose and delivery methods may have contributed to diminished efficacy, one crucial aspect of these clinical studies is that GDNF treatment across all studies began [~]8 years after PD diagnosis; a time point representing several years after near 100% depletion of nigrostriatal dopamine markers in striatum and at least 50% in substantia nigra (SN), and is later than the timing of GDNF treatment in preclinical studies. With nigrostriatal terminal loss exceeding 70% at PD diagnosis, we utilized hemi-parkinsonian rats to determine if expression of GDNF family receptor, GFR-1, and receptor tyrosine kinase, RET, differed between striatum and SN at 1 and 4 weeks following a 6-hydroxydopamine (6-OHDA) lesion. Whereas GDNF expression changed minimally, GFR-1 expression decreased progressively in striatum and in tyrosine hydroxylase positive (TH+) cells in SN, correlating with reduced TH cell number. However, in nigral astrocytes, GFR-1 expression increased. RET expression decreased maximally in striatum by 1 week, whereas in the SN, a transient bilateral increase occurred that returned to control levels by 4 weeks. Expression of brain-derived neurotrophic factor (BDNF) or its receptor, TrkB, were unchanged throughout lesion progression. Together, these results reveal that differential GFR-1 and RET expression between the striatum and SN, and cell-specific differences in GFR-1 expression in SN, occur during nigrostriatal neuron loss. Targeting loss of GDNF receptors appears critical to enhance GDNF therapeutic efficacy against nigrostriatal neuron loss. Significance StatementAlthough preclinical evidence supports that GDNF provides neuroprotection and improves locomotor function in preclinical studies, clinical data supporting its efficacy to alleviate motor impairment in Parkinsons disease patients remains uncertain. Using the established 6-OHDA hemi-parkinsonian rat model, we determined whether expression of its cognate receptors, GFR-1 and RET, were differentially affected between striatum and substantia nigra in a timeline study. In striatum, there was early and significant loss of RET, but a gradual, progressive loss of GFR-1. In contrast, RET transiently increased in lesioned substantia nigra, but GFR-1 progressively decreased only in nigrostriatal neurons and correlated with TH cell loss. Our results indicate that direct availability of GFR-1 may be a critical element that determines GDNF efficacy following striatal delivery. HighlightsGDNF expression was minimally affected by nigrostriatal lesion GDNF family receptor, GFR-1, progressively decreased in striatum and in TH neurons in SN. GFR-1 expression decreased along with TH neurons as lesion progressed GFR-1 increased bilaterally in GFAP+ cells suggesting an inherent response to offset TH neuron loss RET expression was severely reduced in striatum, whereas it increased in SN early after lesion induction

neuroscience↗
bioRxiv2022

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

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. 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.

neuroscience↗