Gdf-15 deficiency does not alter vulnerability of nigrostriatal dopaminergic system in MPTP-intoxicated mice

Abstract

Growth/differentiation factor-15 (Gdf-15) is a member of the transforming growth factor-β (Tgf-β) superfamily and has been shown to be a potent neurotrophic factor for midbrain dopaminergic (DAergic) neurons both in vitro and in vivo. Gdf-15 has also been shown to be involved in inflammatory processes. The aim of this study was to identify the role of endogenous Gdf-15 in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease (PD) by comparing Gdf-15 (+/+) and Gdf-15 (-/-) mice. At 4 days and 14 days post-MPTP administration, both Gdf-15 (+/+) and Gdf-15 (-/-) mice showed a similar decline in DAergic neuron numbers and in striatal dopamine (DA) levels. This was followed by a comparable restorative phase at 90 days and 120 days, indicating that the absence of Gdf-15 does not affect the susceptibility or the recovery capacity of the nigrostriatal system after MPTP administration. The MPTP-induced microglial and astrocytic response was not significantly altered between the two genotypes. However, pro-inflammatory and anti-inflammatory cytokine profiling revealed the differential expression of markers in Gdf-15 (+/+) and Gdf-15 (-/-) mice after MPTP administration. Thus, the MPTP mouse model fails to uncover a major role of endogenous Gdf-15 in the protection of MPTP-lesioned nigrostriatal DAergic neurons, in contrast to its capacity to protect the 6-hydroxydopamine-intoxicated nigrostriatal system.

Subregional differences in astrocytes underlie selective neurodegeneration or protection in Parkinson's disease models in culture

“…Furthermore, immunostaining of FACS isolated midbrain TH‐GFP DA neurons demonstrates strong receptor expression on these neurons after culture (Figure c,d), whereas striatal cultures lack expression of the receptor (Figure f,h) demonstrating antibody selectivity. These findings demonstrate that the receptor for GDF15 is indeed present within SN and VTA neurons, suggesting that the lack of GDF15 production by SN astrocytes may explain the absence of protection in this subregion and the failure to find an increased vulnerability in SN DA neurons in GDF15 knockout mice (Machado et al, ). In contrast, VTA astrocytes may be able to protect both VTA and SN DA neurons due to their high level of GDF15 expression coupled with the presence of the GFRAL receptor.…”

Serum FGF-21, GDF-15, and blood mtDNA copy number are not biomarkers of Parkinson disease

“…9 Evidence of its neuroprotective effect in different toxin-induced rodent models of PD is conflicting. 10,11 Serum levels of GDF-15 were found to be increased in Chinese patients with PD compared with controls. 12 In contrast, GDF-15 levels in the CSF were similar in German nondemented PD patients and controls, but increased in patients with PD and dementia and patients with Lewy body dementia.…”

Emerging roles of growth differentiation factor‑15 in brain disorders (Review)

“…Strelau et al (84) demonstrated that unilateral injections of GDF15 into the medial forebrain bundle immediately above the substantia nigra prior to 6-OHDA administration were able to confer protection against complete lesion formation induced by 6-OHDA, which prevented the loss of the dopaminergic neurons. Consistently, Machado et al (117,118) further demonstrated that endogenous GDF15 may promote the survival of dopaminergic neurons by regulating the inflammatory response after 6-OHDA-induced brain injury. GDF15 released by astrocytes exerted a protective effect on vulnerable nigral neurons during PD and on induced pluripotent stem cell-derived dopaminergic neurons subjected to 1-methyl-4-phenylpyridinium toxicity, which may explain the selective degeneration or protection of dopaminergic neurons in PD because GDF15 is expressed 230-fold higher in the neighboring ventral tegmental area astrocytes than the substantia nigra pars compacta (20,119).…”