Parkinson's Disease (PD) and the FGF20 Gene

Parkinson's disease (PD) is a neurodegenerative disorder that predominantly affects dopamine-producing (“dopaminergic”) neurons in a specific area of the brain, called the substantia nigra.The Centers for Disease Control and Prevention (CDC) rated complications from PD as the 14th leading cause of death in the United States. Herein, we analyze the disease code from a genetic point of view, current scientific research developments, and disease models used to expand our understanding of the illness and improve human health. In our Weekly Gene articles, Cyagen will explore the relationship between diseases and genes with you.

Overview of FGF20 Gene

Fgf20, originally identified in the rat brain, encodes a secreted protein of 212 amino acids^[1]. The fibroblast growth factor (FGF) gene family is comprised of 22 members and has been classified into 7 subfamilies; FGF/1/2, FGF4/5/6, FGF3/7/10/22, FGF8/17/18, FGF9/16/20, FGF11/12/13/14, and FGF19/21/23. FGF20 is a member of the FGF9/16/20 subfamily, which is a paracrine Fgf (Figure 1) ^[2].

Figure 1. Evolutionary relationships within the human FGF gene family by phylogenetic analysis. Phylogenetic analysis suggests that 22 FGF genes can be arranged into seven subfamilies containing two to four members each. Branch lengths are proportional to the evolutionary distance between each gene^[2]. 

Table. 1. Summaries for FGF20 Gene

Fgf20, which acts on proximal cells, significantly enhanced the survival of cultured dopaminergic neurons by activating the mitogen-activated protein kinase (MAPK) pathway through Fgf receptor 1c. In the rat model of Parkinson's disease, Fgf20 afforded significant protection against the loss of dopaminergic neurons. The significant correlation of Parkinson's disease with single-nucleotide polymorphisms in FGF20 indicates that the genetic variability of FGF20 can be a Parkinson's disease risk. Neural and embryonic stem (ES) cells have been considered as cell resources for restorative transplantation strategies in Parkinson's disease. Fgf20 promoted the differentiation of these stem cells into dopaminergic neurons, which attenuated neurological symptoms in animal models of Parkinson's disease. These findings indicate the importance of FGF20 for the differentiation and survival of dopaminergic neurons and the etiology and therapy of Parkinson's disease^[3].

Function of the FGF20 Gene

The protein encoded by the FGF20 gene is a member of the fibroblast growth factor (FGF) family. The fibroblast growth factors possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene product is a secreted neurotrophic factor but lacks a typical signal peptide. It is expressed in the normal brain, particularly the cerebellum, and may regulate central nervous system development and function. Homodimerization of this protein was shown to regulate its receptor binding activity and concentration gradient in the extracellular matrix. Genetic variations of this gene have been associated with susceptibility to Parkinson disease (PD).

FIG. 2. AlphaFold structure prediction (Fibroblast growth factor 20) Source: Uniprot^[4]

Disorders Related to the FGF20 Gene

Parkinson's disease is a common neurodegenerative disorder that occurs when nerve cells in the brain don't produce enough of a brain chemical called dopamine. Sometimes it is genetic-based and inheritable, but most cases do not seem to run in families. Exposure to chemicals in the environment might play a role. Symptoms begin gradually, often on one side of the body, affecting both sides as the disease progresses. Symptoms include: trembling of hands, arms, legs, jaw and face; stiffness of the arms, legs and trunk; slowness of movement; poor balance and coordination. As symptoms get worse, people with the disease may have trouble walking, talking, or doing simple tasks. They may also have problems such as depression, sleep problems, or trouble chewing, swallowing, or speaking. There is no specific test for PD, so it can be difficult to diagnose. Doctors use a medical history and a neurological examination for diagnosis. PD usually begins around age 60, but it can start earlier, and it is more common in men than in women. There is no cure for PD, but a variety of medicines sometimes help symptoms dramatically. Additionally, Surgery and deep brain stimulation (DBS) can help severe cases. With DBS, electrodes are surgically implanted in the brain to send electrical pulses to stimulate the parts of the brain that control movement. 

FIG. 3. Parkinson's disease, Source: Medical Dialogues^[5]

The inability to control movement in patients with this disease has been attributed to the severe loss of dopaminergic neurons within the substantia nigra. Environmental and genetic sources act together in the disease cascade. FGF20 has been mapped to 8p21.3–8p22, which is within an area of Parkinson's disease linkage. It means that the gene FGF20 is related to Parkinson's disease.

To test whether FGF20 genetic variability was a risk factor for Parkinson's disease (PD), Itoh N’s team examined five single-nucleotide polymorphisms (SNPs) lying in FGF20 in a large family study. The highly significant correlation of Parkinson's disease with one SNP located in the intron and two SNPs in the 3′ regulatory region was revealed, which indicated that Fgf20 genetic variability is a risk factor for PD. In addition, FGF20 genetic variability was shown to be a risk factor for Parkinson's disease in Japanese and Chinese populations, while it was not a risk factor for PD in Finnish and Greek populations. The discrepancy between these results remains to be elucidated.

The latest research has identified a series of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson’s disease, after Bonferroni correction. Human embryonic stem cells (hESCs) are a potential source of dopaminergic neurons for treatment of patients with Parkinson’s disease (PD). Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson's disease. They aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci, and fully sequenced 32 genes from 25 loci previously associated with Parkinson's disease in 2657 patients and 3647 controls from three cohorts.The association of FGF20 was driven by a rare 5' UTR variant (rs1034608171) located in the promoter region. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson's disease-related genes[6].

To Be Continued: Mouse Models of Fgf20

In the next article, we will update you on the applications of mouse models used for Fgf20 gene studies and new research progress.

>>Learn more: Gene Fgf20 Mouse Models and New Research Progress

References:

[1] Ohmachi S, Watanabe Y, Mikami T, et al. FGF-20, a novel neurotrophic factor, preferentially expressed in the substantia nigra pars compacta of rat brain[J]. Biochemical and biophysical research communications, 2000, 277(2): 355-360.

[2] Itoh N, Ornitz D M. Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease[J]. The Journal of Biochemistry, 2011, 149(2): 121-130.

[3] Itoh N, Ohta H. Roles of FGF20 in dopaminergic neurons and Parkinson's disease[J]. Frontiers in molecular neuroscience, 2013, 6: 15.

[4] https://alphafold.ebi.ac.uk/entry/Q9ESL9

[5]https://medicaldialogues.in/neurology-neurosurgery/news/coffee-consumption-tied-to-lower-risk-of-developing-parkinsons-disease-study-70083

[6] Rudakou U, Yu E, Krohn L, et al. Targeted sequencing of Parkinson’s disease loci genes highlights SYT11, FGF20 and other associations[J]. Brain, 2021, 144(2): 462-472.