Recently, I discussed neurotrophic factors that could potentially be used therapeutically in the therapy of neurodegenerative diseases. The essential signal transduction processes through which these molecules promote neuronal survival were presented. A key question is how long growth factor receptors remain active in the cell. This depends on their intracellular transport, their degradation in the lysosome, and possible recycling to the cell membrane .
The growth factor GDNF (glia-derived-neurotrophic-factor) has received particular attention over the years (the name is derived from a rat glial cell line in which it was first discovered in 1993). Since GDNF promotes the survival and maturation of dopaminergic neurons that perish in Parkinson's disease, its potential therapeutic use in patients is currently being investigated in clinical trials (they can be viewed under the keyword 'Parkinson's' and 'GDNF' at https://clinicaltrials.gov/).
In these studies, GDNF is introduced into the target area of dopaminergic neurons either as purified protein (with a length of 134 amino acids) or via gene shuttle, i.e. as DNA. The injection site is usually the putamen, a part of the striatum (see the following figure), in which dopamine is only available to a reduced extent in Parkinson's patients. Here, the level of endogenous GDNF also decreases considerably during the course of the disease. Thus, normalization of the factor is expected to have a beneficial effect on the remaining dopaminergic axons that project from the midbrain (substantia nigra) into the striatum. Interestingly, beneficial effects of GDNF on glial cells appear to play an important role as well via anti-inflammatory mechanisms through inhibition of the p38 MAP kinase signaling in microglia and through positive effects on astrocytes (a decrease in activated astroglia leading to gliosis and degeneration was observed after GDNF treatment).
Although several previous clinical trials were unsuccessful, clinical research with GDNF continues. There is hope, because many of the difficulties in therapy with growth factors, especially with regard to their required concentration, stability and mode of application, have been overcome over the years by new developments in genetic engineering and pharmacology. Therefore, it is likely that GDNF based therapies will be available for Parkinson's disease patients in the near future.
Frontal view of a frontal section through the brain. The shell nucleus (putamen), tail nucleus (caudate nucleus), outer pale spherical nucleus (called globus pallidus or pallidum), and the amygdaloid nucleus (corpus amygdaloideum), which belongs to the limbic system, are located in the telencephalon. The putamen and caudate nucleus together form the striate body (striatum). The corpus callosum connects the two cerebral hemispheres. The inner part of the pallidum and the nucleus subthalamicus comprise the diencephalon, of which the thalamus and hypothalamus are the essential core areas. The substantia nigra is located in the midbrain and projects to the striatum (red arrow). The cerebellum, with its largest nucleus, the dentate nucleus, lies posterior to the brainstem. The dentate nucleus sends signals coming from the cerebellum to the motor nuclei of the thalamus (nucleus ventrolateralis). From the ventral thalamus the signals reach the motor cortex and from there they project via the capsula interna (black arrow) into the brainstem and spinal cord (Fig. 2.8a from Klimaschewski L.P. , Parkinson's and Alzheimer's disease today. Springer, 2021).
References:
Conway J, Kramer E (2022) Is activation of GDNF/RET signaling the answer for successful treatment of Parkinson's disease? A discussion of data from the culture dish to the clinic. Neural Regeneration Research 17:1462-1467
Delgado-Minjares KM, Martinez-Fong D, Martínez-Dávila IA et al. (2021) Mechanistic insight from preclinical models of Parkinson's disease could help redirect clinical trial efforts in GDNF therapy. International Journal of Molecular Sciences 22:11702
Chiavellini P, Canatelli-Mallat M, Lehmann M, Goya R, Morel G (2022) Therapeutic potential of glial cell line-derived neurotrophic factor and cell reprogramming for hippocampal-related neurological disorders. Neural Regeneration Research 17:469-476
Image credit: iStock/Dr_Microbe
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