GFR α-1 receptor expression in the aging nigrostriatal and mesoaccumbens pathways

Abstract

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