Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disease of motor neurons with no effective
treatment. New treatments are desperately needed, but clinical trials are hampered by the heterogeneous
nature of ALS, such as the variablity and unpredictability of disease progression. There is also a paucity of
sensitive measures to track responses to treatment leading to lengthier and more costly trials and a greater
burdern on the patient. Through an R21-funded RNA sequencing project on human ALS muscle (Si et al.,
2014), we have identified fibroblast growth factor 23 (FGF23) as a promising biomarker in ALS that might help
fill this clinical gap. In our preliminary data, we observe that plasma FGF23 levels increase with disease
progression in the SOD1G93A mouse model of ALS, and are elevated in a small cohort of ALS patients where
levels appear to correlate positively with rapid decline in functional rating scores. In Specfic Aim 1, we
hypothesize that plasma FGF23 levels will track disease progression and that higher FGF23 levels will
predict a poorer prognosis in ALS patients. This hypothesis will be tested by measuring plasma FGF23 by
ELISA in a large cohort of well characterized and longitudinally followed ALS patients from a national
biorepository. The cohort will represent the diversity of clinical phenotypes inherent in this disease, including
fast- and slow-progressors. In our preliminary studies, we observed also that FGF23 is elevated in muscle,
spinal cord and cortex of the SOD1G93A mouse, suggesting that FGF23 signaling is activated in ALS. FGF23
acts as a pro-inflammatory cytokine, can be produced by macrophages, and can activate macrophages and
other immune cells to produce inflammatory cytokines such as TNF-a and IL-1ß. Since neuroinflammation
accelerates disease progression in ALS, elevated FGF23 may represent a disease modifier that contributes to
the clinical heterogeneity of ALS. In Specific Aim 2, we hypothesize that FGF23 is produced in the CNS of
the SOD1G93A mouse by glia or invading immune cells, and that it can activate these cells to produce
inflammatory cytokines. We will perform immunohistochemistry to localize FGF23 in CNS and muscle
tissues of the SOD1G93A mouse and with human ALS tissues from the PI's tissue repository. We will stimulate
microglia and astroglia from wild-type and SOD1G93A mice with FGF23 and assess activation, including the
induction of inflammatory cytokines and chemotaxis. This aim represents an initial investigation into the
potential role of FGF23 in the pathophysiology of ALS and will pave the way for future mechanistic studies.
In summary, this bench-to-bedside proposal represents a novel direction in ALS with compelling translational
implications. It vertically integrates basic and clinical science approaches, capitalizing on the collaborative spirit
at UAB and the U. of Miami, to address a major gap in testing new treatments in ALS. At the same time, it will
begin to investigate a new signaling pathway that might provide insight into molecular mechanisms that drive
clinical progression in ALS.