PLASMA JNK3 AS A NOVEL PERIPHERAL BIOMARKER IN ALZHEIMER'S AND PARKINSON'S DISEASES: EARLY DIAGNOSIS AND DISEASE MONITORING

Alzheimer’s (AD) and Parkinson’s diseases (PD) are neurodegenerative disorders that share overlapping molecular mechanisms but still lack accessible, disease-specific peripheral biomarkers for early diagnosis and disease monitoring. This thesis investigated the potential of c-Jun N-terminal kinase 3 (JNK3), a neuron-specific stress-activated kinase, as a novel peripheral biomarker with translational value in both AD and PD. In the AD cohort, which included patients with AD, mild cognitive impairment (MCI), and controls (CTR), JNK3 levels were measured in both cerebrospinal fluid (CSF) and plasma. Plasmatic JNK3 levels were significantly increased in MCI patients compared to both AD patients and controls, suggesting that JNK3 may reflect early synaptic dysfunction preceding overt neurodegeneration. In CSF, it was observed higher JNK3 levels in AD compared to controls. Notably, JNK3 levels in CSF showed an inverse correlation with age in both MCI and AD groups, supporting its role as a marker of early neuronal stress rather than aging. Instead, only plasma samples were analysed in the PD cohort, which included individuals with isolated REM sleep behaviour disorder (iRBD), de novo PD, late-stage PD, and healthy controls (HC). Plasmatic JNK3 levels progressively increased from iRBD through to late-stage PD and were significantly associated with disease severity and the presence of peripheral phosphorylated α-synuclein in skin biopsies. JNK3 levels showed a significant inverse correlation with motor symptom severity and were more sensitive than neurofilament light chain (NfL) in identifying early disease stages. Unlike NfL, JNK3 did not correlate with age in pathological groups, further supporting its specificity. Importantly, JNK3 was quantified using a commercially ELISA kit, demonstrating its scalability, low invasiveness, and cost-effectiveness for potential clinical use. In conclusion, this study identified plasma JNK3 as a peripheral biomarker in both AD and PD. Its ability to detect early pathological changes, particularly in prodromal stages MCI and iRBD, respectively in AD and PD supports its potential application in early diagnosis, patient stratification, and longitudinal disease monitoring in both clinical and research settings.