Peripheral Klotho and Parkinson's Disease

The anti-geronic protein α-Klotho (referred to as Klotho), plays a potential role in delaying age-related declines in cellular and tissue function, which has generated considerable interest in targeting this protein for the treatment of agerelated neurodegenerative diseases. Systemic exogenous elevation of Klotho enhances cognition and neural resilience in young, aging, and in vivo models of Parkinson’s disease (PD). Interestingly, in addition to age-related abnormalities, cognitive decline, and premature death, Klotho-deficient mice display nigrostriatal neurodegeneration, a hallmark of PD. We recently identified a role for Klotho in the regulation of mitochondrial DNA damage and bioenergetics. Given increased mitochondrial DNA damage and mitochondrial dysfunction in PD, we explored circulating levels of Klotho in human PD for the first time. To determine whether circulating plasma Klotho levels were associated with PD, we analyzed 122 plasma samples from the Fox Investigation for New Discovery of Biomarkers (BioFIND) cohort, a cross-sectional, observational study of moderate to advanced PD patients and ageand sex-matched healthy controls in which biospecimens were collected with standardized clinical and sample acquisition protocols. Education, race, and co-morbidities did not differ significantly between PD and healthy control groups. Total full-length Klotho levels were determined in the BioFIND plasma samples using a modified immunoprecipitation-immunoblot method, similar to our published studies. When analyzed dichotomously, plasma Klotho levels were not different between healthy controls and PD patients (Fig. 1A). However, levels of Klotho tended to be higher in women compared to men in the PD group; this difference between men and women with regards to Klotho levels was not observed in the healthy control group (Fig. 1A). Biological sex is a critical factor in the development and phenotypic expression of PD. These results are in contrast to the most common form of dementia, Alzheimer’s disease, in which Klotho levels were decreased in the cerebrospinal fluid and plasma, perhaps highlighting differences in underlying mechanisms of these two neurodegenerative diseases. However, it is important to note that the immunoprecipitation–immunoblotting assay used in this study is more efficient in capturing soluble Klotho and selectively measures the full-length Klotho, as compared to the commercial ELISA commonly used. Therefore, caution needs to be exercised in directly comparing the two different methodologies for measures of Klotho. Further, it was recently reported that Klotho haplotypes interact with the APOE genotype to modify Alzheimer’s disease risk. Correlating Klotho levels with Klotho haplotype information is an important consideration for a future study. We next tested the correlation between Klotho levels and PD-relevant clinical measures and whether sex modified these relationships. A lack of an association was observed between total MDS-UPDRS scores and Klotho values in PD patients (Fig. 1B). Additionally, Klotho levels did not correlate with MoCA scores in PD patients; stratifying by sex yielded similar results (Fig. 1C). We also did not find correlations between Klotho levels and advancing age in the PD group (Fig. 1D). Despite a link between pathological aging