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

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 medium spiny 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 multi-ciliated 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. Teaser Loss of primary cilia may contribute to dopamine neuron loss in both inherited and common Parkinson’s disease. Competing Interest Statement H.Y.Z. cofounded Cajal Neuroscience, is a Director of Regeneron Pharmaceuticals board, and is on the scientific advisory board of Cajal Neuroscience, Lyterian and the Column Group.