Challenges and Opportunities of Early Parkinson’s Disease Biomarkers: α-Synuclein, Leucine-Rich Repeat Kinase 2 (LRRK2), DJ-1, and microRNAs

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss, leading to motor symptoms (tremor, rigidity, bradykinesia, postural instability) and non-motor symptoms (autonomic dysfunction, cognitive dysfunction, olfactory dysfunction, mood disorders such as depression). Pathologically, PD involves Lewy bodies, aggregates of phosphorylated α-synuclein (α-Syn) driven by genetic or environmental factors. α-Syn, detectable in cerebrospinal fluid (CSF), blood, and saliva, is a promising biomarker for early diagnosis and monitoring. Other candidates, including leucine-rich repeat kinase 2 (LRRK2), DJ-1, and microRNAs (miRNAs), reflect genetic, oxidative stress, and gene regulatory changes in PD. Ideal biomarkers should be sensitive, specific, non-invasive, and track disease progression. However, PD's heterogeneity, biofluid variability (e.g., hemolysis), methodological inconsistencies, and the need for large-scale validation pose challenges. Standardization of sample collection, assays, and cohort characterization is critical for clinical application. This review evaluates α-Syn, LRRK2, DJ-1, and miRNAs, highlighting their strengths, limitations, and potential. Advanced assays targeting specific α-Syn species, LRRK2 kinase activity, oxidized DJ-1, and miRNA panels, alongside non-invasive matrices (saliva, skin, retina) and multi-biomarker approaches, offer significant opportunities for early detection and therapy monitoring, warranting further research and standardization.