Selective loss of primary cilia and neurotrophic signaling in G51D α-synuclein mice highlights a common pathway to Parkinson's disease

• 成果类型: Article
• 署名作者: Lin, Yu-En; Jaimon, Ebsy; Kim, YoungDoo; Loftman, Annabeth; Vijayakumaran, Aaran; Belfort, Benjamin D. W.; Chiang, Claire Y.; Arenkiel, Benjamin R.; Zoghbi, Huda Y.; Pfeffer, Suzanne R.
• 署名单位: Stanford University; Baylor College of Medicine; Baylor College Medical Hospital
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2619797123
• 发表日期: 2026-08-18
• 页码: e2619797123
• 关键词: Parkinson's disease; neurotrophic signaling; alpha-synuclein; PRIMARY CILIA; neurodegeneration; dysfunction; autophagy; rather; neuron; cells

摘要

Parkinson's disease is characterized by dopaminergic neuron loss and accumulation of alpha-synuclein aggregates in the brain. G51D alpha-synuclein knock-in mice provide a genetically and clinically relevant model of disease, exhibiting early olfactory deficits, age-dependent motor impairment, and progressive phospho-alpha-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 alpha-synuclein mice share these phenotypes. Phospho-Ser129 alpha-synuclein accumulation correlates with cilia loss in cholinergic interneurons but not in spiny projection neurons that accumulate higher phospho-alpha-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.