TY - JOUR
T1 - GFR-α1 Expression in Substantia Nigra Increases Bilaterally following Unilateral Striatal GDNF in Aged Rats and Attenuates Nigral Tyrosine Hydroxylase Loss following 6-OHDA Nigrostriatal Lesion
AU - Kasanga, Ella A.
AU - Owens, Catherine L.
AU - Cantu, Mark A.
AU - Richard, Adam D.
AU - Davis, Richard W.
AU - McDivitt, Lisa M.
AU - Blancher, Blake
AU - Pruett, Brandon S.
AU - Tan, Christopher
AU - Gajewski, Austin
AU - Manfredsson, Fredric P.
AU - Nejtek, Vicki A.
AU - Salvatore, Michael F.
N1 - Funding Information:
This work was funded by grant support to M.F.S. by the National Institute on Aging (AG040261) and a Fellowship Award to CLO by the Parkinson’s Disease Foundation (now recognized as the Parkinson’s Foundation).
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/10/16
Y1 - 2019/10/16
N2 - Glial cell line-derived neurotrophic factor (GDNF) improved motor function in Parkinson's disease (PD) patients in Phase I clinical trials, and these effects persisted months after GDNF discontinuation. Conversely, phase II clinical trials reported no significant effects on motor improvement vs placebo. The disease duration and the quantity, infusion approach, and duration of GDNF delivery may affect GDNF efficacy in PD treatment. However, identifying mechanisms activated by GDNF that affect nigrostriatal function may reveal additional avenues to partially restore nigrostriatal function. In PD and aging models, GDNF affects tyrosine hydroxylase (TH) expression or phosphorylation in substantia nigra (SN), long after a single GDNF injection in striatum. In aged rats, the GDNF family receptor, GFR-α1, increases TH expression and phosphorylation in SN. To determine if GFR-α1 could be a mechanistic link in long-term GDNF impact, we conducted two studies; first to determine if a single unilateral striatal delivery of GDNF affected GFR-α1 and TH over time (1 day, 1 week, and 4 weeks) in the striatum or SN in aged rats, and second, to determine if soluble GFR-α1 could mitigate TH loss following 6-hydroxydopamine (6-OHDA) lesion. In aged rats, GDNF bilaterally increased ser31 TH phosphorylation and GFR-α1 expression in SN at 1 day and 4 weeks after GDNF, respectively. In striatum, GFR-α1 expression decreased 1 week after GDNF, only on the GDNF-injected side. In 6-OHDA-lesioned rats, recombinant soluble GFR-α1 mitigated nigral, but not striatal, TH protein loss following 6-OHDA. Together, these results show GDNF has immediate and long-term impact on dopamine regulation in the SN, which includes a gradual increase in GFR-α1 expression that may sustain TH expression and dopamine function therein.
AB - Glial cell line-derived neurotrophic factor (GDNF) improved motor function in Parkinson's disease (PD) patients in Phase I clinical trials, and these effects persisted months after GDNF discontinuation. Conversely, phase II clinical trials reported no significant effects on motor improvement vs placebo. The disease duration and the quantity, infusion approach, and duration of GDNF delivery may affect GDNF efficacy in PD treatment. However, identifying mechanisms activated by GDNF that affect nigrostriatal function may reveal additional avenues to partially restore nigrostriatal function. In PD and aging models, GDNF affects tyrosine hydroxylase (TH) expression or phosphorylation in substantia nigra (SN), long after a single GDNF injection in striatum. In aged rats, the GDNF family receptor, GFR-α1, increases TH expression and phosphorylation in SN. To determine if GFR-α1 could be a mechanistic link in long-term GDNF impact, we conducted two studies; first to determine if a single unilateral striatal delivery of GDNF affected GFR-α1 and TH over time (1 day, 1 week, and 4 weeks) in the striatum or SN in aged rats, and second, to determine if soluble GFR-α1 could mitigate TH loss following 6-hydroxydopamine (6-OHDA) lesion. In aged rats, GDNF bilaterally increased ser31 TH phosphorylation and GFR-α1 expression in SN at 1 day and 4 weeks after GDNF, respectively. In striatum, GFR-α1 expression decreased 1 week after GDNF, only on the GDNF-injected side. In 6-OHDA-lesioned rats, recombinant soluble GFR-α1 mitigated nigral, but not striatal, TH protein loss following 6-OHDA. Together, these results show GDNF has immediate and long-term impact on dopamine regulation in the SN, which includes a gradual increase in GFR-α1 expression that may sustain TH expression and dopamine function therein.
KW - 6-hydroxydopamine
KW - Parkinson's disease
KW - Substantia nigra
KW - aging
KW - nigrostriatal
KW - tyrosine hydroxylase
UR - http://www.scopus.com/inward/record.url?scp=85073077900&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.9b00291
DO - 10.1021/acschemneuro.9b00291
M3 - Article
C2 - 31538765
AN - SCOPUS:85073077900
SN - 1948-7193
VL - 10
SP - 4237
EP - 4249
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 10
ER -