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News on growth factors in the therapy of neurodegenerative diseases


As described in chapter 3.1.3 of my book about neuronal degeneration, many Parkinson's and Alzheimer's researchers have been trying for many years to prevent or at least delay neuronal cell death by means of neurotrophic factor treatment. Neurotrophins bind to receptor tyrosine kinases (RTKs), which activate protective signaling pathways (see figure below). They are thus able to positively influence neuronal survival and the growth of axons and dendrites. Many of the long-term effects of these factors are mediated via regulation of neuronal gene expression in the nucleus, i.e. via altered expression of gene transcripts (mRNAs).


In particular, activated RTKs and G-protein-coupled receptors stimulate PI3 kinase/AKT and Ras/Raf/MAP kinase-dependent signaling pathways. They are essential for neuronal survival and axonal growth. Members of the neurotrophin family (NGF, BDNF, NT-3) and neurotrophic cytokines, such as ciliary neurotrophic factor (CNTF), have shown impressive effects on affected neurons in animal models of neurodegenerative diseases. Similarly, neurotrophic effects can be demonstrated for insulin-dependent growth factors (IGF-1 and IGF-2), transforming growth factors (TGFs), and several members of the fibroblast growth factor family (FGFs).


Intracellular signaling pathways in neurons originating from transmitter and growth factor receptors. Receptor tyrosine kinases (green) are usually activated by dimerization, i.e. one receptor molecule each binds a growth factor (ligand) and interacts with a second ligand-receptor complex in the plasma membrane. Subsequently, the kinase domains projecting into the cytoplasm phosphorylate each other and activate different signaling pathways: the PLC/DAG/PKC, the Grb2/Ras/Raf/MAP kinase (ERK), and the PI3 kinase/AKT signal transduction cascades. G- protein-coupled receptors located in the cell membrane represent, for example, neuropeptide and dopamine receptors. They consist of a membrane protein (blue) to which a G-protein can dock. This binds GTP and then activates adenylate cyclase, which forms the secondary messenger cAMP and thus activates protein kinase A (PKA). In addition, various calcium-dependent signaling pathways are turned on via phospholipase C (Fig. 3.3 from Klimaschewski L.P. , Parkinson's and Alzheimer's disease today. Springer, 2021)


In neurological diseases associated with neuronal degeneration, hardly any neurotrophic factors are found in the affected brain regions. Therefore, pharmacological approaches are currently being pursued to activate RTKs by treatment with these molecules or by alternative mechanisms to keep receptors in the neuron as long as possible before they are degraded in the lysosome. Since the relevant signal transduction pathways are also activated from intracellular vesicles (endosomes), attempts are being made to delay the transport of activated receptors from early endosomes to late endosomes (see the following figure). On the other hand, the transfer of intracellular RTKs to recycling endosomes may be pharmacologically increased. Thus, elevated levels of RTKs are made available for exogenously added trophic molecules.


Early and late intracellular endosomes can be distinguished by membrane-bound markers (so-called Rab GTPases). Rab5 is a marker of early, Rab7 of late endosomes. When endosomes return to the cell surface and re-fuse with the plasma membrane, they are referred to as recycling endosomes and contain Rab11. Early endosomes are those that form just after endocytosis. Recycling endosomes contain Rab11 (Fig. 3.4 from Klimaschewski L.P. , Parkinson's and Alzheimer's diseases today. Springer, 2021)


The possibility of being able to artificially (genetically) produce neurotrophically active molecules in large quantities was a driving force for the biotechnology industry, which was emerging in the 1980s, to use growth factors in patients with Parkinson's or Alzheimer's disease. Unfortunately, virtually all of these treatment attempts remained without reproducible success. It was not yet known in which dosage and in which way these factors had to be applied. It was also not known at that time whether sufficient quantities of the factors would even pass through the blood-brain barrier into the brain tissue after intravenous administration, i.e. into the blood. Unfortunately, this was usually not the case. Today, we know much more about this biotechnological side of growth factor treatment.


However, there is still a lack of studies on the question of exactly which effects occur as a result of a particular factor in the various brain areas. Presumably, growth factors must be injected in high doses and stereotactically (i.e., by means of a probe) directly into specific brain regions. When administered into the blood or into the cerebrospinal fluid (CSF), proteins are rapidly diluted and normally degraded within hours. Even when injected at high concentrations, the factors would therefore be degraded by protein-cleaving enzymes (peptidases) circulating in the serum and CSF. Also, it is still debated whether neurons in the brain of the elderly even carry sufficient amounts of intact receptors for the neurotrophic factors on their surface. The growth factors have therefore not yet found their way into the therapy of Alzheimer's and Parkinson's disease outside of clinical studies.


With respect to PD, a potential use of glia-derived neurotrophic factor (GDNF) is currently under investigation. GDNF promotes survival and maturation of dopaminergic neurons and is delivered to the brain via gene therapy. Other therapeutic trials with neurotrophic factors have also been initiated in recent years, such as Cerebral Dopamine Neurotrophic Factor (CDNF). CDNF has been shown to work well experimentally, although it does not bind to surface receptors, but appears to exert its effects in the intracellular endoplasmic reticulum (ER) and can positively influence ER stress in neurons.


References:


Klimaschewski L, Claus P (2021) Fibroblast Growth Factor signalling in the diseased nervous system. Molecular Neurobiology 58:3884–3902


Delgado-Minjares KM, Martinez-Fong D, ... , Soto-Rojas LO (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


Lauzon MA, Daviau A, Marcos B, Faucheux N (2015) Growth factor treatment to overcome Alzheimer's dysfunctional signalling. Cellular Signalling 27:1025-1038


Image credit: iStock/whitehoune



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