Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease worldwide; therefore, since its initial description, significant progress has been made, yet a mystery remains regarding its pathogenesis and elusive root cause. The widespread distribution of pathological α-synuclein (αSyn) aggregates throughout the body raises inquiries regarding the etiology, which has prompted several hypotheses, with the most prominent one being αSyn-associated proteinopathy. The identification of αSyn protein within Lewy bodies, coupled with genetic evidence linking αSyn locus duplication, triplication, as well as point mutations to familial Parkinson’s disease, has underscored the significance of αSyn in initiating and propagating Lewy body pathology throughout the brain. In monogenic and sporadic PD, the presence of early inflammation and synaptic dysfunction leads to αSyn aggregation and neuronal death through mitochondrial, lysosomal, and endosomal functional impairment. However, much remains to be understood about αSyn pathogenesis, which is heavily grounded in biomarkers and treatment strategies. In this review, we provide emerging new evidence on the current knowledge about αSyn’s pathophysiological impact on PD, and its presumable role as a specific disease biomarker or main target of disease-modifying therapies, highlighting that this understanding today offers the best potential of disease-modifying therapy in the near future.

Background and Objectives: Parkinson’s disease (PD) includes a prodromal phase characterized by non-motor symptoms (NMS). We investigated whether sleep disturbances co-aggregate with other NMS in suspected prodromal PD (p-PD) to refine early phenotyping and risk stratification. Materials and Methods: A population-based survey was conducted in Kaunas, Lithuania. Participants from the Kaunas City preventive health screening cohort (2024–2025) were screened using the Innsbruck REM Sleep Behaviour Disorder Inventory (RBD-I). Sixty-two individuals were included: 31 with suspected p-PD and 31 controls. Demographic characteristics, clinical features, sleep symptoms, olfactory function, autonomic symptoms, cognition, and mood were assessed. Between-group comparisons and within-group correlation analyses were performed. Results: Groups did not differ in age, sex, education, lifestyle exposures, or family history (all p > 0.05). Compared with controls, individuals with suspected p-PD had a higher prevalence of insomnia (71.0% vs. 12.9%, p < 0.001), pathological daytime sleepiness (22.6% vs. 0%, p = 0.005), cognitive impairment (54.8% vs. 16.1%, p = 0.001), and constipation (32.3% vs. 0%, p = 0.002). As expected from the predefined enrichment strategy, hyposmia and orthostatic hypotension (OH) were observed only among suspected p-PD participants. Within the suspected p-PD group, the Non-Motor Symptoms Questionnaire (NMSQ) scores correlated with depressive/anxiety symptoms (r = 0.578, p = 0.001). Olfactory dysfunction correlated with cognitive impairment (r = 0.410, p = 0.001) and depressive/anxiety symptoms (r = 0.396, p = 0.001). Conclusions: Sleep disturbances, particularly insomnia and excessive daytime sleepiness, co-occurred with cognitive, affective, and gastrointestinal non-motor manifestations in individuals with suspected p-PD, supporting the concept of a broader prodromal phenotype. Comprehensive screening in individuals with RBD symptoms may improve early PD risk stratification beyond single-marker approaches.