What Is the Potential Relevance of Growth and Differentiation Factor-15 in Neurologic Disease?

Growth and differentiation factor-15 (GDF-15) is a multifunctional cytokine that is a distant member of both the transforming growth factor-beta (TGF-β) superfamily and glial cell-derived neurotrophic factor (GDNF) family.^1-6 GDF-15 is released in physiologic conditions, such as pregnancy or muscle exercise, but its levels increase particularly in the setting of cellular stress associated with mitochondrial dysfunction and tissue injury.^7,8 GDF-15 is a central inhibitor of appetite^9,10 and regulates energy homeostasis,^2-5 inflammation,¹¹ and carcinogenesis¹² (Figure). The effects of GDF-15 signaling can be beneficial or detrimental, depending on their timing, magnitude, and duration.⁵ Circulating levels of GDF-15 increase with aging and can be markedly elevated in several pathologic conditions, including obesity, diabetes, renal disease, cardiovascular disease, and cancer, where they are typically associated with poor outcomes.^13-17 The role of GDF-15 in the pathogenesis and as a biomarker and therapeutic target in these disorders has been extensively reviewed^4-6 and will not be further discussed here. Circulating GDF-15 levels also increase in patients with diabetic peripheral neuropathy,¹⁸ mitochondrial myopathy,¹⁹ neurodegenerative disorders,^20-22 and glioma.²³ Although experimental evidence suggests that GDF-15 may have a potential neuroprotective role against neurodegeneration^22,24 and a detrimental role in glioma,²⁴ its role as a biomarker and therapeutic target in neurologic disorders is yet to be established.