GDF15 upregulation in Parkinson's disease: Compensatory mechanisms and causal insights

Abstract

Parkinson's disease (PD) is a prevalent long-term neurodegenerative condition resulting from the impairment of dopaminergic neurons (DNS) in the substantia nigra (SN). It is closely tied to inflammatory processes and oxidative stress, which worsen as PD neuropathology advances. Consequently, biomarkers linked to inflammation and oxidative stress may aid in diagnosing and monitoring PD progression. Growth differentiation factor 15 (GDF15) has emerged as a novel diagnostic biomarker for PD, though the exact reason for its elevation in PD remains unclear. This review seeks to investigate the cause-effect link between PD and heightened GDF15 levels. GDF15, part of the transforming growth factor-beta (TGF-β) family, exerts its effects through activation of the glial cell line-derived neurotrophic factor family receptor alpha-like (GFRAL). It serves a critical neuroprotective function in various brain disorders, including PD, where it enhances DNS survival, mitochondrial efficiency, and cellular energy metabolism. During PD progression, DNS degeneration may stimulate the release of anti-inflammatory GDF15 to counteract neuronal damage, though the precise mechanisms require further exploration. Elevated GDF15 levels in PD could reflect a response to cellular stress and mitochondrial dysfunction in DNS. GDF15 appears to suppress PD-related neuroinflammation by inhibiting the NLRP3 inflammasome, NF-κB signaling, and pro-inflammatory cytokine production. This suggests that increased GDF15 expression in PD may act as a compensatory mechanism to mitigate oxidative stress, mitochondrial impairment, and inflammatory pathways. As such, therapeutic strategies targeting GDF15 activation could hold promise for managing PD pathology. Further research is needed to clarify its regulatory pathways and therapeutic potential.