ArticleProceedings of the National Academy of Sciences of the United States of America2024
Loss of primary cilia and dopaminergic neuroprotection in pathogenic LRRK2-driven and idiopathic Parkinson's disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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36 citing papers in PubMed.
- Lasker~Bloomberg Public Service Award to Michael J. Fox: The challenge of Parkinson's disease.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Constrained peptide mimics of the LRRK2 C-terminal Helix inhibits its kinase activity.Bioorganic chemistry · 2026Article
- Selective loss of primary cilia and neurotrophic signaling in G51D α-synuclein mice highlights a common pathway to Parkinson's disease.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Nigrostriatal dopaminergic vulnerability in Parkinson's disease: Neuroprotective strategies.Neural regeneration research · 2026Article
- Article
- An LRRK2 variant blocks NCOA4 trafficking upon iron overload, leading to ferroptotic death.Journal of cell science · 2026Article
- Knockout of the LRRK2-counteracting RAB phosphatase PPM1H disrupts axonal autophagy and exacerbates alpha-synuclein aggregation.Cell reports · 2026Article
- In situ proteomics unveils specialized domains for extrasynaptic signaling on neuronal cilia.Science advances · 2026Article
- Proximity proteomics reveals a co-evolved LRRK2-regulatory network linked to centrosomes.EMBO reports · 2026Article
- The GPCR Smoothened on cholinergic interneurons modulates dopamine-associated acetylcholine dynamics, learning, and effort management.iScience · 2026Article
- Ferritin in ferroptosis: Implications for neurodegenerative diseases (Review).International journal of molecular medicine · 2026Review
- A stereotyped glial attachment determines the morphology and function of neuronal cilia.bioRxiv : the preprint server for biology · 2026Article
- Linking primary cilia defects to the "Big 3" neurodegenerative diseases - causal, consequential, or correlative?EXCLI journal · 2026Article
- Dopamine 2 receptor ablation from cholinergic neurons attenuates L-DOPA induced dyskinesias.Frontiers in aging neuroscience · 2026Article
- The Impact of Neurotoxin Proteins Trafficked by Primary Cilia and Extracellular Vesicles in Neurodegenerative Diseases.Biology · 2025Review
- Taking Down the Primary Cilium: Pathways for Disassembly in Differentiating Cells.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Strategies for multimodal spatiotemporal profiling of phosphorylation in cilia biology.Journal of cell science · 2025Review
- Design principles of ciliary signaling.Journal of cell science · 2025Review
- PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson's disease.Cell reports · 2025Article
- Lysosomal glucocerebrosidase is needed for ciliary Hedgehog signaling: A convergent pathway contributing to Parkinson's disease.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
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Abstract
Activating leucine-rich repeat kinase 2 (LRRK2) mutations cause Parkinson's and phosphorylation of Rab10 by pathogenic LRRK2 blocks primary ciliogenesis in cultured cells. In the mouse brain, LRRK2 blockade of primary cilia is highly cell type specific: For example, cholinergic interneurons and astrocytes but not medium spiny neurons of the dorsal striatum lose primary cilia in LRRK2-pathway mutant mice. We show here that the cell type specificity of LRRK2-mediated cilia loss is also seen in human postmortem striatum from patients with LRRK2 pathway mutations and idiopathic Parkinson's. Single nucleus RNA sequencing shows that cilia loss in mouse cholinergic interneurons is accompanied by decreased glial-derived neurotrophic factor transcription, decreasing neuroprotection for dopamine neurons. Nevertheless, LRRK2 expression differences cannot explain the unique vulnerability of cholinergic neurons to LRRK2 kinase as much higher LRRK2 expression is seen in medium spiny neurons that have normal cilia. In parallel with decreased striatal dopaminergic neurite density, LRRK2 G2019S neurons show increased autism-linked CNTN5 adhesion protein expression; glial cells show significant loss of ferritin heavy chain. These data strongly suggest that loss of cilia in specific striatal cell types decreases neuroprotection for dopamine neurons in mice and human Parkinson's.
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