Abstract We recently reported that age-related bradykinesia was associated with reduced DA tissue content, ser31 tyrosine hydroxylase (TH) phosphorylation, and total TH levels in substantia nigra (SN) only. Here, we propose that these decreases result from reduced GDNF family receptor alpha-1 (GFR alpha-1) levels in the aged (30 month-old) cohort of rats. Analysis of GFR alpha-1 receptor protein in SN, striatum, ventral tegmental area (VTA), and nucleus accumbens (NAc) from 12- and 30-month old Brown-Norway/Fischer 344 F(1) hybrid rats revealed immunoreactivity at approximately 48 and 52 kDa, bands previously characterized to correspond to soluble and GPI-linked forms of GFR alpha-1, respectively. The nigrostriatal pathway had significantly greater levels of the soluble GFR alpha-1 than the mesoaccumbens pathway. Aging significantly reduced soluble and total GFR alpha-1 in the SN. The levels of GFR alpha-1 significantly correlated with TH protein in SN, striatum, and NAc, but only in the SN did GFR alpha-1 significantly correlate with DA levels. Based on these observations and findings from the literature, we speculate that 1) GFR alpha-1 receptor expression may regulate nigral DA bioavailability in vivo, 2) age-related decreases in soluble GFR alpha-1 in SN may contribute to bradykinesia in aging, and 3) differences in expression of the GFR alpha-1 forms between the nigrostriatal and mesoaccumbens pathways and allied tissue may indicate that GDNF-signaling differs between these DA pathways.
