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

Overview

1. Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305
2. Aligning Science Across Parkinson’s Collaborative Research Network, Chevy Chase, MD 20815
3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 76798
4. Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX 76798
5. Department of Neuroscience, Baylor College of Medicine, Houston, TX 76798
6. Department of Neurology and Pediatrics, Baylor College of Medicine, Houston, TX 76798
7. HHMI, Chevy Chase, MD 20815

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

No file of the authors' code could be read here: it is described below, and read at its source.

The paper's code and data availability statement is in the Data section.

Tracing map

Proposed by the machine: these links were found in the paper and verified at the source, without human review. The map will receive a Zenodo DOI once one of the paper's authors has validated it with their ORCID.

What the map holds:

• 1 repository of the authors' code, each at its verified commit, with its license and how the link was found in the paper;
• 0 scripts, each with its path and the digest of its content;
• no match between paragraphs and code yet;
• neither the text of the paper nor the code itself.

Its JSON (tracing-map.json) is deposited on Zenodo with its DOI once the map is validated.

Data

No dataset and no data link were found in the paper.

Data, Materials, and Software Availability

All data have been deposited in DRYAD (https://doi.org/10.5061/dryad.4xgxd25r0) (65). All other data are included in the article and/or SI Appendix (http://www.pnas.org/lookup/doi/10.1073/pnas.2619797123#supplementary-materials).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 4 keywords, 10 MeSH terms, 3 funders, 62 references.

Cite

This paper

Lin, Y.-E., Jaimon, E., Kim, Y., Loftman, A., Vijayakumaran, A., Belfort, B. D. W., Chiang, C. Y., Arenkiel, B. R., Zoghbi, H. Y., & Pfeffer, S. R. (2026). 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, 123(33), e2619797123. https://doi.org/10.1073/pnas.2619797123

The tracing map gets a citation of its own once an author has validated it and it has a DOI.

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.1016/j.isci.2026.115324

The GPCR Smoothened on cholinergic interneurons modulates dopamine-associated acetylcholine dynamics, learning, and effort management.

Journal: iScience

In common: 8 references

[2] doi:10.1016/j.nbd.2026.107379 [code]

DYRK1A and Parkinson's disease, facts and hypotheses.

Journal: Neurobiology of disease

In common: Parkinson's, cellular / molecular, 6 references

[3] doi:10.1126/sciadv.aed5548 [code]

In situ proteomics unveils specialized domains for extrasynaptic signaling on neuronal cilia.

Journal: Science advances

In common: mouse, cellular / molecular, 5 references

[4] doi:10.1038/s41531-026-01382-z

Preformed fibrils of α-synuclein rapidly activate LRRK2 on early endosomes, driving Rab5 phosphorylation and disrupting endolysosomal and synaptic function.

Journal: NPJ Parkinson's disease

In common: Parkinson's, cellular / molecular, 5 references

[5] doi:10.1038/s44318-026-00817-w

The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair.

Journal: The EMBO journal

In common: mouse, cellular / molecular, 4 references

[6] doi:10.1038/s41467-026-75194-3 [code]

Leucine-rich repeat kinase 2 impairs the release sites of Parkinson's disease vulnerable dopamine axons.

Journal: Nature communications

In common: Parkinson's, mouse, cellular / molecular, 4 references

[7] doi:10.1186/s40035-026-00577-x

Brain region-resolved pharmacodynamics of an antisense oligonucleotide targeting human SNCA 3'UTR in BAC-hSNCA rats.

Journal: Translational neurodegeneration

In common: Parkinson's, cellular / molecular, 3 references

[8] doi:10.1101/gad.353596.125

Functional divergence of Capicua isoforms explains differential tissue vulnerability in neurological disease.

Journal: Genes & development

In common: mouse, cellular / molecular, author Huda Y Zoghbi

[9] doi:10.1126/sciadv.aeb4265 [code]

Single-nucleus profiling reveals a core disease signature and cell type-specific vulnerabilities in early Rett syndrome.

Journal: Science advances

In common: mouse, cellular / molecular, author Huda Y Zoghbi

[10] doi:10.1038/s41531-026-01420-w

Locus coeruleus α-synuclein overexpression induces prodromal Parkinsonian features in mice.

Journal: NPJ Parkinson's disease

In common: Parkinson's, mouse, cellular / molecular, 3 references

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.