TGF-beta superfamily members promote survival of midbrain dopaminergic neurons and protect them against MPP+ toxicity.

Abstract

The superfamily of transforming growth factors‐beta (TGF‐beta) comprises an expanding list of multifunctional proteins serving as regulators of cell proliferation and differentiation. Prominent members of this family include the TGF‐beta s 1‐5, activins, bone morphogenetic proteins and a recently discovered glial cell line‐derived neurotrophic factor (GDNF). In the present study we demonstrate and compare the survival promoting and neuroprotective effects of TGF‐beta 1, ‐2 and ‐3, activin A and GDNF for midbrain dopaminergic neurons in vitro. All proteins increase the survival of tyrosine hydroxylase‐immunoreactive dopaminergic neurons isolated from the embryonic day (E) 14 rat mesencephalon floor to varying extents (TGF‐beta s 2.5‐fold, activin A and GDNF 1.6‐fold). TGF‐beta s, activin A and GDNF did not augment numbers of very rarely observed astroglial cells visualized by using antibodies to glial fibrillary acidic protein and had no effect on cell proliferation monitored by incorporation of BrdU. TGF‐beta 1 and activin A protected dopaminergic neurons against N‐methyl‐4‐phenylpiridinium ion toxicity. Reverse transcription‐polymerase chain reaction (RT‐PCR) analysis indicated that TGF‐beta 2 mRNA, but not GDNF mRNA, is expressed in the E14 rat midbrain floor and in mesencephalic cultures. We conclude that TGF‐beta s 1‐3, activin A and GDNF share a neurotrophic capacity for developing dopaminergic neurons, which is not mediated by astroglial cells and not accompanied by an increase in cell proliferation.

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

“…TGFb2 and TGF-b3 are expressed in adult nigral DNs, and TGF-b1 and TGF-b2 expression is increased in biopsies of Parkinson's disease patients (Unsicker et al 1991;Nagatsu et al 2000). Treatment of DN cultures with TGF-b1, TGFb2, or TGF-b3 enhances cell survival following exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an experimental model of Parkinson's disease in vivo (Krieglstein et al 1995a;Roussa et al 2009). TGF-b cooperates with GDNF, a potential therapeutic agent for Parkinson's disease, to promote DN survival (Krieglstein et al 1998).…”

Transforming growth factor-β induces cellular injury in experimental diabetic neuropathy

“…In neuronal tissues, it is clear that TGF-βs play a neurotrophic role in some situations (Chalazonitis et al, 1992;Krieglstein et al, 1995;Martinou et al, 1990;Poulsen et al, 1994), while they elicit cell-death-inducing effects in other situations Schuster and Krieglstein 2002). However, the exact role of various isoforms of TGF-β and its functions are not understood in the peripheral nervous system or in diabetic neuropathy.…”

TGF-β1 actions on FRTL-5 cells provide a model for the physiological regulation of thyroid growth

“…In some cell types, TGF-b1 induced growth arrest is accompanied by programmed cell death (for review see Lieberman et al, 1995) while in other cases members of the TGF-b superfamily can protect against apoptosis (Krieglstein et al, 1995). The pathways through which TGF-b exerts these e ects are unclear due to the absence of a model in which the growth inhibitory action could be dissected from the apoptotic e ect.…”