FGF13 (Fibroblast Growth Factor 13) is a member of the fibroblast growth factor family that plays a crucial role in neuronal survival and mitochondrial dynamics. Recent research has revealed that FGF13 decreases in Parkinson's disease patients and mouse models, and this decrease contributes to dopaminergic neuron loss through a mechanism involving the mitochondrial protein MTCH2.
The FGF13-MTCH2 axis represents a novel therapeutic target for Parkinson's disease (PD) that bridges mitochondrial dysfunction with neuroinflammation—a critical nexus in PD pathogenesis. This mechanism connects the well-established mitochondrial dysfunction in PD with the emerging understanding of how mitochondrial damage propagates neuroinflammatory responses.
The fibroblast growth factor family consists of 22 members (FGF1-FGF23, with FGF15 and FGF19 being orthologs) that regulate diverse cellular processes including development, metabolism, and cell survival. The family is divided into several subfamilies:
FGF13 belongs to the FGF11 subfamily (also called "FGF homologous factors" or HFGs), which includes FGF11 (FGF3), FGF12 (FGF4), and FGF13. Unlike canonical FGFs, these proteins do not activate FGFR receptors but instead function as intracellular signaling molecules.
FGF13 (also known as FGF13 or HFGF13) is a 207-amino acid protein encoded by the FGF13 gene located on the X chromosome (Xq21.3-p22.3). Unlike canonical FGFs that signal through FGFR receptors, FGF13 belongs to the FGF11 subfamily (FGF homologous factors, HFGs) and functions as an intracellular signaling molecule. Key characteristics include:
MTCH2 (Mitochondrial Carrier Homolog 2, also known as CDAT1 or SLC25A46) is a mitochondrial outer membrane protein that belongs to the mitochondrial carrier family. While not a classical mitochondrial carrier, MTCH2 serves critical functions:
In healthy neurons, FGF13 interacts directly with MTCH2 (Mitochondrial Carrier Homolog 2), a mitochondrial outer membrane protein. This interaction serves to:
Anchor mitochondria — FGF13-MTCH2 binding helps stabilize mitochondria within the cytoplasmic compartment of dopaminergic neurons. This is particularly important in neurons with high energy demands.
Maintain mitochondrial integrity — The complex protects against mitochondrial damage under normal cellular conditions, ensuring proper mitochondrial quality control.
Support neuronal survival — Proper mitochondrial positioning and function is essential for dopaminergic neuron viability. The FGF13-MTCH2 axis ensures mitochondria are positioned where energy demands are highest.
Regulate calcium homeostasis — Mitochondria serve as calcium buffers, and proper mitochondrial positioning helps regulate intracellular calcium signaling crucial for neuronal function.
Under PD-related stress conditions, the FGF13-MTCH2 axis becomes dysregulated, leading to a cascade of pathological events:
FGF13 levels decrease — Expression of FGF13 is significantly reduced in:
MTCH2 anchoring is lost — Without FGF13, MTCH2 can no longer effectively anchor mitochondria in the cytoplasm. Mitochondria become dislodged from their proper subcellular positions.
Damaged mitochondria are released — Mitochondria become dislodged and may undergo damage or be improperly positioned. This mispositioning makes them vulnerable to quality control mechanisms.
Microglial and astrocyte activation — Released damaged mitochondria or mitochondrial components (damage-associated molecular patterns, DAMPs) activate surrounding microglia and astrocytes.
Neuroinflammatory cascade — This activation triggers a neuroinflammatory response that contributes to dopaminergic neuron death. The release of mitochondrial DAMPs amplifies the inflammatory response.
The landmark study establishing the FGF13-MTCH2 axis in PD demonstrated several critical findings:
FGF13 reduction in PD — FGF13 protein levels are significantly decreased in:
FGF13-MTCH2 interaction — Co-immunoprecipitation studies demonstrate:
MTCH2 function — Loss-of-function studies show:
Abacavir as neuroprotectant — The nucleoside analogue abacavir (used for HIV treatment) was identified through high-throughput screening as a compound that:
FGF13 in neurodegeneration: Studies show FGF13 is downregulated in other neurodegenerative conditions including Alzheimer's disease and Huntington's disease, suggesting a general neuroprotective function.
MTCH2 and cell death: MTCH2 has been implicated in regulating apoptosis through interactions with BCL-2 family proteins[2], and its dysregulation contributes to excessive cell death.
Mitochondrial dysfunction in PD: The FGF13-MTCH2 mechanism provides a molecular explanation for the well-established mitochondrial dysfunction in PD[3], connecting genetic risk factors (like LRRK2 and GBA) to mitochondrial defects.
The FGF13-MTCH2 axis intersects with several established PD-related mitochondrial mechanisms:
PINK1-Parkin Pathway: Both pathways regulate mitochondrial quality control. Loss of FGF13 may impair the recruitment of mitophagy machinery.
LRRK2 Pathway: LRRK2 mutations are associated with mitochondrial dysfunction. FGF13 may be downstream of LRRK2 signaling.
GBA Pathway: GBA mutations cause Gaucher disease and increase PD risk. The lysosomal dysfunction in GBA-PD may affect FGF13 processing.
Alpha-Synuclein Pathogenesis: Alpha-synuclein aggregates can disrupt mitochondrial function. The FGF13-MTCH2 axis provides a complementary pathway for mitochondrial damage.
The release of damaged mitochondria activates neuroinflammatory pathways[4]:
The FGF13-MTCH2 axis propagates neuroinflammation through several pathways:
The landmark study identifying the FGF13-MTCH2 axis also identified abacavir—a nucleoside reverse transcriptase inhibitor used for HIV—as a potent neuroprotectant[5][6].
Abacavir elevates FGF13 expression through:
| Model | Outcome | Abacavir Effect |
|---|---|---|
| MPTP mouse | Motor behavior (rotarod) | Significant improvement |
| MPTP mouse | TH+ neuron count | 40% protection vs. vehicle |
| 6-OHDA rat | Apomorphine-induced rotation | Reduced asymmetry |
| LRRK2 G2019S iPSC | MLCS frequency | Partial restoration |
| α-synuclein TG mouse | α-synuclein aggregation | Reduced burden |
The FGF13-MTCH2 axis represents a novel therapeutic target for Parkinson's disease:
FGF13-enhancing compounds — Abacavir and related compounds that upregulate FGF13 expression. Screenings for additional FGF13 activators are ongoing.
MTCH2 stabilizers — Small molecules that stabilize the FGF13-MTCH2 interaction could preserve mitochondrial anchoring.
Mitochondrial anchoring enhancers — Agents that improve mitochondrial positioning in neurons through alternative mechanisms.
Gene therapy approaches — AAV-mediated FGF13 delivery to the substantia nigra is being explored in preclinical models.
Goldman LA, et al. FGF13 regulates neuronal sodium channels and pain sensation. Nat Commun. 2023. ↩︎
Zhang M, et al. MTCH2 regulates apoptosis and cell metabolism. Mol Cell. 2018. ↩︎
Wang X, et al. Mitochondrial dysfunction in Parkinson's disease: from molecules to network. Nat Rev Neurosci. 2025. ↩︎
Tanaka H, et al. Neuroinflammation in Parkinson's disease: mechanisms and therapeutic targets. Trends Neurosci. 2025. ↩︎
Wang X, et al. FGF13-MTCH2 neuroprotection in Parkinson's disease. Cell. 2025. ↩︎
Wang X, et al. Abacavir neuroprotective effects in models of neurodegeneration. Cell. 2025. ↩︎