Longevity Factor Klotho and Resistance to Cognitive Deficits in Individuals with Parkinson’s Disease and in an α-Synuclein Mouse Model
, linked to higher circulating klotho levels, associated with better executive cognition in individuals with PD across two independent cohorts. To test causality and explore mechanisms, we turned to mouse models. Transgenic elevation of klotho in a mouse model increased lifespan, improved synaptic and cognitive, but not motor, functions in mice, and decreased steady-state α-synuclein (α-syn) levels in the brains of male mice expressing wild-type human α-syn. Complementary in vitro studies showed that klotho rescued α-syn-induced deficits in NMDAR-dependent signaling through GluN2B and augmented α-syn microglial-related uptake, suggesting a potential mechanism by which klotho counters PD-related toxicity. Together, these findings indicate that klotho can counteract cognitive deficits related to PD, possibly by modulating α-syn levels, and these findings may be relevant to new therapeutic pathways for PD.
Authors
- Cana Park
- Lauren Broestl (ORCID: https://orcid.org/0000-0002-6566-3986)
- Sylvain Lesné (ORCID: https://orcid.org/0000-0001-9411-1868)
- Alexandre Bétourné (ORCID: https://orcid.org/0000-0002-2791-2072)
- Claire Huguenard
- Dena B. Dubal (ORCID: https://orcid.org/0000-0001-7504-4372)
- Jill L. Ostrem (ORCID: https://orcid.org/0000-0001-7018-9521)
- Samira Abdulai-Saiku (ORCID: https://orcid.org/0000-0003-3772-4646)
- Shweta Gupta (ORCID: https://orcid.org/0000-0002-5900-4108)
- Arturo J. Moreno (ORCID: https://orcid.org/0000-0003-2357-5854)
- Rohan Sehgal
- Luke W. Bonham (ORCID: https://orcid.org/0000-0002-2533-1266)
- Jennifer S. Yokoyama (ORCID: https://orcid.org/0000-0001-7274-2634)
- Jonathan Y. Lin (ORCID: https://orcid.org/0000-0003-4977-2506)
- Nijee Luthra (ORCID: https://orcid.org/0000-0002-6774-0711)
- Dan Wang
Institutions
- University of Minnesota (US)
- University of California, San Francisco (US)
- University of California System (US)
- University Memory and Aging Center (US)
- Centre for Movement Disorders (CA)
- Institute on Aging (US)
- International Neuromodulation Society (US)
Publication Details
- Journal
- Journal of Neuroscience
- Published
- 2026-03-31
- DOI
- https://doi.org/10.1523/jneurosci.1904-25.2026
- Primary Topic
- Parathyroid Disorders and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Federation for Aging Research
- Glenn Foundation for Medical Research
- National Institute of Neurological Disorders and Stroke