Wnt antagonist FRZB is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis

Kwan, Thaddaeus; Kazamel, Mohamed; Thoenes, Kristina; Si, Ying; Jiang, Nan; King, Peter H.

doi:10.1038/s41598-020-73845-z

Cited by 17 publications

(21 citation statements)

References 42 publications

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“…in kidney cells) can abrogate FGF23 activity 44 . Interestingly, we observed a similar pattern with FRZB, a secreted Wnt antagonist, which is also associated with grouped atrophic fibers, increases in the endomysial compartment with ALS disease progression, and cannot be detected in the peripheral circulation 9 . Although FRZB does not have a defined HSGAG binding site, it has an overall net positive charge at physiological pH similar to FGF23 (+ 7.454 versus + 5.971), and thus may also associate with negatively charged HSGAGs.…”

Section: Discussionsupporting

confidence: 68%

“…Early involvement of skeletal muscle is underscored by our prior work which defines a molecular signature in ALS skeletal muscle beginning in the earliest pre-clinical phases of disease based on correlative studies with the SOD1 G93A mouse. Characterization of this signature emerged from RNA sequencing of human ALS muscle, and encompasses genes of diverse pathways including Smads, TGF-β, vitamin D (CYP27-B1), FRZB/Wnt signaling, and select microRNAs 9 – 13 . Some of the markers, such as Smad 1, 5, 8, and TGF-β, appear to be specific for ALS whereas FRZB and CYP27B1 were increased in non-ALS neurogenic processes.…”

Section: Introductionmentioning

confidence: 99%

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FGF23, a novel muscle biomarker detected in the early stages of ALS

Kazamel

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et al. 2021

Sci Rep

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle weakness. Skeletal muscle is a prime source for biomarker discovery since it is one of the earliest sites to manifest disease pathology. From a prior RNA sequencing project, we identified FGF23 as a potential muscle biomarker in ALS. Here, we validate this finding with a large collection of ALS muscle samples and found a 13-fold increase over normal controls. FGF23 was also increased in the SOD1G93A mouse, beginning at a very early stage and well before the onset of clinical symptoms. FGF23 levels progressively increased through end-stage in the mouse. Immunohistochemistry of ALS muscle showed prominent FGF23 immunoreactivity in the endomysial connective tissue and along the muscle membrane and was significantly higher around grouped atrophic fibers compared to non-atrophic fibers. ELISA of plasma samples from the SOD1G93A mouse showed an increase in FGF23 at end-stage whereas no increase was detected in a large cohort of ALS patients. In conclusion, FGF23 is a novel muscle biomarker in ALS and joins a molecular signature that emerges in very early preclinical stages. The early appearance of FGF23 and its progressive increase with disease progression offers a new direction for exploring the molecular basis and response to the underlying pathology of ALS.

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

FGF23, a novel muscle biomarker detected in the early stages of ALS

Kazamel

Benatar

et al. 2021

Sci Rep

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“…in kidney cells) can abrogate FGF23 activity 44 . Interestingly, we observed a similar pattern with FRZB, a secreted Wnt antagonist, which also increases in the endomysial compartment with ALS disease progression but cannot be detected in the peripheral circulation 9 . Although FRZB does not have a defined HSGAG binding site, it has an overall net positive charge at physiological pH similar to FGF23 (+7.454 versus + 5.971), and thus may also associate with negatively charged HSGAGs.…”

Section: Discussionsupporting

confidence: 74%

“…Early involvement of skeletal muscle is underscored by our prior work which defines a molecular signature in ALS skeletal muscle beginning in the earliest pre-clinical phases of disease based on correlative studies with the SOD1 G93A mouse. Characterization of this signature emerged from RNA sequencing of human ALS muscle, and encompasses genes of diverse pathways including Smads, TGF-β, vitamin D (CYP27-B1), FRZB/Wnt signaling, and select microRNAs [9][10][11][12][13] . Some of the markers, such as Smad 1, 5, 8, and TGF-β, appear to be specific for ALS whereas FRZB and CYP27B1 were increased in non-ALS neurogenic processes.…”

Section: Introductionmentioning

confidence: 99%

FGF23, A Novel Muscle Biomarker Detected in The Early Stages of ALS

Kazamel

Benatar

et al. 2021

Preprint

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle weakness. Skeletal muscle is a prime source for biomarker discovery since it is one of the earliest sites to manifest disease pathology. From a prior RNA sequencing project, we identified FGF23 as a potential muscle biomarker in ALS. Here, we validate this finding with a large collection of ALS muscle samples and found a 13-fold increase over normal controls. FGF23 was also increased in the SOD1G93A mouse, beginning at a very early stage and well before the onset of clinical symptoms. FGF23 levels progressively increased through end-stage in the mouse. Immunohistochemistry of ALS muscle showed prominent FGF23 immunoreactivity in the endomysial connective tissue and along the muscle membrane. ELISA of plasma samples from the SOD1G93A mouse showed an increase in FGF23 at end-stage whereas no increase was detected in a large cohort of ALS patients. In conclusion, FGF23 is a novel muscle biomarker in ALS and joins a molecular signature that emerges in very early preclinical stages. The early appearance of FGF23 and its progressive increase with disease advancement offers a new direction for exploring the molecular basis or response to the underlying pathology of ALS.

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“…FRZB, the WNT antagonist, is a molecular sign of muscle denervation in ALS and begins to increase in skeletal muscle in the early pre–symptomatic period. This discovery offers benefits for diagnosing and tracking disease progression [ 46 ].…”

Section: Wnt Proteins and Nmjs In The Progress Of Alsmentioning

confidence: 99%

Potential Roles of the WNT Signaling Pathway in Amyotrophic Lateral Sclerosis

Jiang

Guan

Zhao

et al. 2021

Cells

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The WNT signaling pathway plays an important role in the physiological and pathophysiological processes of the central nervous system and the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We reviewed the literature pertinent to WNT/β–catenin signaling in ALS from cellular studies, animal models, and human clinical trials. WNT, WNT receptors, and other components of the WNT signaling pathway are expressed in both ALS patients and transgenic mice, and are involved in the pathogenesis of ALS. Studies have shown that abnormal activation of the WNT/β–catenin signaling pathway is related to neuronal degeneration and glial cell proliferation. WNT/Ca2+ signaling is associated with the pro–inflammatory phenotype of microglia; data on the muscle skeletal receptor Tyr kinase receptor in superoxide dismutase–1–G93A mice indicate that gene therapy is necessary for successful treatment of ALS. The varying profiles of lipoprotein receptor–related protein 4 antibodies in different ethnic groups suggest that individual treatment and multifactorial personalized approaches may be necessary for effective ALS therapy. In conclusion, the WNT signaling pathway is important to the ALS disease process, making it a likely therapeutic target.

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Wnt antagonist FRZB is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis

Cited by 17 publications

References 42 publications

FGF23, a novel muscle biomarker detected in the early stages of ALS

FGF23, a novel muscle biomarker detected in the early stages of ALS

FGF23, A Novel Muscle Biomarker Detected in The Early Stages of ALS

Potential Roles of the WNT Signaling Pathway in Amyotrophic Lateral Sclerosis

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