Secreted GPNMB enhances uptake of fibrillar alpha-synuclein in a non-cell-autonomous process that can be blocked by anti-GPNMB antibodies
Neuron 2026Marc Carceles-Cordon et al.
This 2026 follow-up paper demonstrates that GPNMB can be cleaved off the cell surface, and the extracellular domain (ECD) can do everything that we reported full-length GPNMB to do in 2022. Moreover, we present evidence suggesting that the source of the GPNMB ECD is microglia, which upregulate GPNMB secretion in response to neuronal damage. Finally, we show that anti-GPNMB antibodies can block uptake of aSyn fibrils in neurons and prevent the subsequent formation of aSyn pathology.
GPNMB confers risk for Parkinson's disease through interaction with α-synuclein
Science 2022Maria Diaz-Ortiz, Yunji Seo et al.
This 2022 paper demonstrates that GPNMB is the target gene of a Parkinson's disease GWAS locus, that higher GPNMB expression is associated with PD risk, and that GPNMB is necessary and sufficient for uptake of aSyn fibrils in cellular models (iPSC-derived neurons). Effects may be through a protein-protein interaction between aSyn and GPNMB.
Blood α-synuclein separates Parkinson's disease from dementia with Lewy bodies
Annals of Neurology 2025George Kannarkat, Rebecca Zack et al.
Clinicians learn the "one year rule" — if a patient develops cognitive issues more than one year after motor symptoms, they are diagnosed with PD, while if they develop cognitive problems before or within the first year after motor symptoms, they are diagnosed with DLB. If that sounds arbitrary to you, you're not alone. But this 2025 study completely changed Alice's prior belief that PD and DLB are the same disease — because it turns out that conformations of alpha-synuclein may distinguish the two.
Cognitive heterogeneity in Parkinson's disease: a mechanistic view
Review in Neuron 2023Marc Carceles-Cordon, Dan Weintraub, Alice Chen-Plotkin
A review that captures a lot of how we're thinking about the synucleinopathies — Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. We are actively trying to target many of these mechanisms now.