A potent neurotrophic factor that enhances survival of midbrain dopaminergic neurons was purified and cloned. Glial cell line-derived neurotrophic factor (GDNF) is a glycosylated, disulfide-bonded homodimer that is a distantly related member of the transforming growth factor-beta superfamily. In embryonic midbrain cultures, recombinant human GDNF promoted the survival and morphological differentiation of dopaminergic neurons and increased their high-affinity dopamine uptake. These effects were relatively specific; GDNF did not increase total neuron or astrocyte numbers nor did it increase transmitter uptake by gamma-aminobutyric-containing and serotonergic neurons. GDNF may have utility in the treatment of Parkinson's disease, which is marked by progressive degeneration of midbrain dopaminergic neurons.

During normal development of the vertebrate nervous system, large numbers of neurons in the central and peripheral nervous system undergo naturally occurring cell death. For example, about half of all spinal motor neurons die over a period of a few days in developing avian, rat and mouse embryos. Previous studies have shown that extracts from muscle and brain, secreted factors from glia, as well as several growth factors and neurotrophic agents, including muscle-derived factors, can promote the survival of developing motor neurons in vitro and in vivo. But because neurotrophins and other known trophic agents administered alone or in combination are insufficient to rescue all developing motor neurons from cell death, other neurotrophic molecules are probably essential for the survival and differentiation of motor neurons. Here we report that glial-cell-line-derived neurotrophic factor (GDNF), a potent neurotrophic factor that enhances survival of mammalian midbrain dopaminergic neurons, rescues developing avian motor neurons from natural programmed cell death in vivo and promotes the survival of enriched populations of cultured motor neurons. Furthermore, treatment with this agent in vivo also prevents the induced death and atrophy of both avian and mouse spinal motor neurons following peripheral axotomy.

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Glial cell line-derived neurotrophic factor (GDNF) has been shown to rescue developing motoneurons in vivo and in vitro from both naturally occurring and axotomyinduced cell death. To test whether GDNF has trophic effects on adult motoneurons, we used a mouse model of injuryinduced adult motoneuron degeneration. Injuring adult motoneuron axons at the exit point of the nerve from the spinal cord (avulsion) resulted in a 70% loss of motoneurons by 3 weeks following surgery and a complete loss by 6 weeks. Half of the loss was prevented by GDNF treatment. GDNF also induced an increase (hypertrophy) in the size of surviving motoneurons. These data provide strong evidence that the survival of injured adult mammalian motoneurons can be promoted by a known neurotrophic factor, suggesting the potential use of GDNF in therapeutic approaches to adultonset motoneuron diseases such as amyotrophic lateral sclerosis.Factors that promote motoneuron survival have potential as therapeutic agents for the treatment of human neurodegenerative diseases (1). It has been shown that several neurotrophic factors, including brain-derived neurotrophic factor (BDNF) (2-4), insulin-like growth factor (I.GF) (5), ciliary neurotrophic factor (6), and glial cell line-derived neurotrophic factor (GDNF) (7-10), can rescue developing motoneurons from both naturally occurring and axotomy-induced cell death. However, whether these trophic factors also play a role in adult motoneuron survival is not known. Because many motoneuron diseases, such as amyotrophic lateral sclerosis, have a late (i.e., adult) onset, it is important to determine whether neurotrophic factors are effective on injured adult motoneurons.Interactions between motoneurons and their target muscles have been extensively investigated. For example, it is known that transection of axons of motoneurons or removal of their target during embryonic and early postnatal development results in massive motoneuron cell loss, whereas axotomy of adult peripheral nerve induces little if any neuronal death (11)(12)(13)(14)(15)(16)(17)(18)(19). A plausible explanation for this difference is that trophic support derived from mature nonneuronal cells (e.g., Schwann cells) associated with the peripheral nerve maintains the survival of adult motoneurons.A different type of lesion, ventral root avulsion, which involves pulling the root out of the spinal cord, induces the death of virtually all motoneurons in the adult rat and provides a good model to examine the response of adult motoneurons to trophic factors (20,21). The expression of nitric oxide synthase (NOS), an enzyme for synthesis of the free radical nitric oxide (NO), can be induced in adult rat motoneurons following both spinal root avulsion (20,22) and cranial nerve axotomy (23), and it has been suggested that the cell death following these lesions may be induced by oxidative stress and reactive oxygen species such as [20][21][22].Although the target dependency of motoneuron survival is diminished in adult animals (15, 18), adult rat m...

Ciliary neurotrophic factor (CNTF) is one of a small number of proteins with neurotrophic activities distinct from nerve growth factor (NGF). CNTF has now been purified and cloned and the primary structure of CNTF from rabbit sciatic nerve has been determined. Biologically active CNTF has been transiently expressed from a rabbit complementary DNA clone. CNTF is a neural effector without significant sequence homologies to any previously reported protein.