PDGFRA (Platelet-Derived Growth Factor Receptor Alpha) encodes a cell surface tyrosine kinase receptor for platelet-derived growth factors (PDGF-AA, PDGF-BB, PDGF-AB, and PDGF-CC). The PDGF/PDGFR signaling axis is a critical mediator of cell proliferation, migration, and survival in developing and adult tissues, including the central nervous system. PDGFRA is predominantly expressed in mesenchymal cells, including glial progenitors, oligodendrocyte precursor cells (OPCs), fibroblasts, and vascular smooth muscle cells. [1]
The human PDGFRA gene is located on chromosome 4q12 and consists of 23 exons encoding a transmembrane glycoprotein of approximately 1086 amino acids. The protein features an extracellular domain with five immunoglobulin-like loops for ligand binding, a single transmembrane helix, and an intracellular tyrosine kinase domain with autophosphorylation sites. Alternative splicing produces multiple isoforms with distinct ligand affinities and signaling properties. [2]
PDGFRA is highly expressed in neural crest-derived cells and mesodermal tissues during development. In the adult brain, PDGFRA marks a population of proliferating glial progenitor cells in the subventricular zone (SVZ) and white matter tracts. These PDGFRA+ cells represent a major source of new oligodendrocytes and astrocytes in the adult CNS. PDGFRA+ progenitors also populate the meninges and perivascular niches, where they contribute to tissue homeostasis and repair responses. [3]
PDGF signaling has been implicated in Alzheimer's disease (AD) pathogenesis through multiple mechanisms. PDGF receptors are expressed on astrocytes and microglia, where they regulate inflammatory responses and amyloid-beta (Aβ) clearance. Studies have shown that PDGF-BB can enhance microglial phagocytosis of Aβ plaques and promote anti-inflammatory phenotypes. However, dysregulated PDGF signaling may also contribute to astrogliosis and neuronal dysfunction in AD brains. [4]
In Parkinson's disease (PD), PDGF signaling influences dopaminergic neuron survival and glial responses. PDGF-BB has been shown to protect substantia nigra dopaminergic neurons from toxic insults in experimental models. PDGFRA+ glial progenitors proliferate and migrate in response to nigrostriatal injury, potentially contributing to compensatory mechanisms or pathological gliosis. The PDGF/PDGFR axis also regulates blood-brain barrier integrity, which may affect Lewy body pathology spread. [5]
In ALS, PDGFRA+ progenitors represent an important source of proliferating cells in the spinal cord and brainstem. These cells can give rise to new oligodendrocytes and astrocytes, but this regenerative capacity diminishes with disease progression. PDGF signaling promotes oligodendrocyte progenitor proliferation, which may be protective in ALS by enhancing remyelination. However, astrocyte reactivity driven by PDGF signaling may also contribute to motor neuron vulnerability. [6]
PDGF signaling is dysregulated in multiple system atrophy (MSA), particularly in the oligodendroglial pathology characteristic of this disorder. PDGFRA+ glial progenitors show altered proliferation and differentiation in MSA brains, potentially contributing to oligodendrocyte loss and demyelination. Studies have identified PDGF-C as a potent activator of MSA-relevant pathology.
The PDGF/PDGFRA signaling axis represents a potential therapeutic target in neurodegenerative diseases. Agonists that enhance PDGF-BB or PDGF-CC signaling may promote glial progenitor activation, oligodendrocyte regeneration, and neuroprotection. Conversely, selective PDGFRA inhibitors (e.g., imatinib) have been explored for their effects on glial tumor proliferation. Clinical trials of PDGF modulators in CNS disorders are ongoing.
Zhang et al. PDGF signaling in Alzheimer's disease (2020). 2020. ↩︎
Sato et al. PDGF-BB protects dopaminergic neurons (2018). 2018. ↩︎
McIver et al. PDGFRA+ progenitors in ALS (2019). 2019. ↩︎
Richter et al. PDGF-C in multiple system atrophy (2019). 2019. ↩︎
Yao et al. PDGF signaling and glial responses (2021). 2021. ↩︎
Nicoletti et al. PDGFRA expression in adult brain (2018). 2018. ↩︎