Phosphorylated Ubiquitin as a Clinical Biomarker for Mitochondrial Damage in Neurodegenerative Diseases

Dec 16, 2025Aging and disease

Phosphorylated Ubiquitin as a Clinical Marker of Mitochondrial Damage in Brain Degenerative Diseases

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Abstract

pS65-Ub levels in cerebrospinal fluid (CSF) were decreased in patients with Parkinson's disease compared to controls.

Phosphorylated ubiquitin (pS65-Ub) is linked to mitochondrial degradation processes.
Levels of pS65-Ub accumulate with aging and are elevated in the brains of individuals with Alzheimer's or Parkinson's disease.
In plasma samples from various cohorts, pS65-Ub measurements were not specific enough to serve as a reliable diagnostic marker.
CSF analysis showed better discrimination of pS65-Ub levels between Parkinson's disease patients and controls.
Further studies in larger cohorts are necessary to validate pS65-Ub as a potential biomarker in CSF.

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Phosphorylated ubiquitin (pS65-Ub) is generated by the kinase-ligase pair PINK1-Parkin to selectively label damaged mitochondria for degradation via the autophagy-lysosome system (mitophagy). Consistent with increasing mitochondrial and lysosomal dysfunctions, pS65-Ub accumulates with aging in human autopsy brain and in mice. pS65-Ub levels are strongly and independently elevated in brains from subjects with Alzheimer's or Parkinson's disease compared to age-matched, neurologically normal controls. Furthermore, pS65-Ub levels have been used to identify disease risk and potential resilience factors in cells and in human brain. However, it remains unknown whether pS65-Ub measured in biofluids may also be suitable as a clinical biomarker. Here, we used a validated sandwich ELISA based on the Mesoscale discovery platform to assess pS65-Ub levels in over 1500 plasma samples from different cohorts across a spectrum of mild cognitive impairment, Alzheimer's disease, or Parkinson's disease. We further analyzed almost 150 CSF samples from two independent case-control series with Parkinson's disease to determine whether pS65-Ub levels are associated with disease status and other clinical parameters. While pS65-Ub levels are significantly changed with disease compared to controls in certain samples, current measurements in plasma are not sufficiently discriminatory to serve as a robust diagnostic marker. However, in CSF, pS65-Ub levels were decreased in patients with Parkinson's disease compared to controls, and there was better discrimination between these groups. Our data indicate that pS65-Ub shows promise as a biomarker in CSF but will require further replication in larger cohorts and possibly in combination with additional other measures.

Phosphorylated Ubiquitin as a Clinical Biomarker for Mitochondrial Damage in Neurodegenerative Diseases

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