The Many Faces of Parkinson’s: A Holistic Scientific Review

Abstract

Introduction and Definition: Parkinson’s disease (PD) is a “neurodegenerative disorder characterized by early and marked loss of dopaminergic neurons,” leading to abnormal motor presentation, including bradykinesia, muscular rigidity, rest tremor, and postural and gait impairment¹. The primary cause of these Parkinsonian symptoms is the insufficient production of dopamine, predominantly resulting from the degeneration of dopamine-producing neurons in the basal ganglia.

Body: First systematically documented by James Parkinson in 1817 and later refined by Jean-Martin Charcot; this condition affects approximately 10 million people worldwide, and about 90,000 new cases are diagnosed annually in the United States. PD manifests itself in both classical forms with Parkinsonian motor impairments, and in atypical variants with diverse symptom profiles. The study of protein aggregation in PD began with Friedrich Lewy’s identification of Lewy bodies in 1912. This protein aggregation was linked to inherited genetic mutations in genes synuclein alpha (SNCA) and leucine-rich repeat kinase 2, which 15% of PD cases are attributed to. Most cases, however, have no identifiable cause and are believed to result from a combination of genetic susceptibility, environmental factors, and pathological protein misfolding and aggregation. These aggregates cause oxidative stress, mitochondrial dysfunction, and neuronal death. Recent research highlights the spread of α-synuclein (α-syn) aggregates across neural networks, emphasizing genetic predispositions, environmental toxins, and impaired protein clearance mechanisms as critical contributors to disease progression. Small-molecule inhibitors, immunotherapies targeting α-syn, and gene-editing technologies such as clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR-Cas9) are being researched as potential treatments and therapies for PD. Advancements in neuroimaging and biomarker discovery also represent crucial steps for earlier detection and improved patient management. Other ongoing research aims to detail aggregation pathways, identify reliable biomarkers, and validate novel therapeutic strategies in clinical trials, ultimately striving to improve and transform disease management to significantly enhance patient outcomes.