Selective Loss of Primary Cilia and Neurotrophic Signaling in G51D α-Synuclein Mice Highlights a Common Pathway to Parkinson’s Disease

Authors

• Yu-En Lin
• Ebsy Jaimon
• YoungDoo Kim
• Annabeth Loftman
• Aaran Vijayakumaran
• Benjamin D W Belfort
• Claire Y Chiang
• Benjamin R Arenkiel
• Huda Y Zoghbi
• Suzanne R Pfeffer

Language

English

Publication Date

8-18-2026

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2619797123

PMID

42574603

PMCID

PMC13486547

PubMedCentral® Posted Date

8-10-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Parkinson's disease is characterized by dopaminergic neuron loss and accumulation of α-synuclein aggregates in the brain. G51D α-synuclein knock-in mice provide a genetically and clinically relevant model of disease, exhibiting early olfactory deficits, age-dependent motor impairment, and progressive phospho-α-synuclein accumulation. In multiple Parkinson's disease models, striatal cholinergic and parvalbumin interneurons, as well as astrocytes, lose primary cilia and the neurotrophic signaling needed to sustain dopaminergic neurons. We show here that G51D α-synuclein mice share these phenotypes. Phospho-Ser129 α-synuclein accumulation correlates with cilia loss in cholinergic interneurons but not in spiny projection neurons that accumulate higher phospho-α-synuclein levels. In the piriform cortex, parvalbumin neurons lose primary cilia and downregulate Neurturin, potentially contributing to olfactory dysfunction. Within the peripheral olfactory epithelium, horizontal basal cells lose cilia, whereas multiciliated olfactory sensory neuron cilia remain intact. These findings reveal convergent cellular vulnerabilities across Parkinson's disease models and highlight a pathogenic role for impaired ciliary signaling.

Keywords

Animals, alpha-Synuclein, Cilia, Mice, Parkinson Disease, Signal Transduction, Dopaminergic Neurons, Disease Models, Animal, Interneurons, Mice, Transgenic, neurotrophic signaling, alpha-Synuclein, primary cilia

Published Open-Access

yes

Recommended Citation

Lin, Yu-En; Jaimon, Ebsy; Kim, YoungDoo; et al., "Selective Loss of Primary Cilia and Neurotrophic Signaling in G51D α-Synuclein Mice Highlights a Common Pathway to Parkinson’s Disease" (2026). Duncan NRI Faculty and Staff Publications. 230.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/230