What causes Parkinson's disease?

What Causes Parkinson's Disease?

Parkinson's disease is caused by a complex interplay of aging, genetic susceptibility, and environmental factors, with the pathological hallmark being progressive degeneration of dopaminergic neurons in the substantia nigra and accumulation of alpha-synuclein protein in Lewy bodies. 1, 2

Primary Pathophysiological Mechanism

Parkinson's disease is fundamentally a synucleinopathy characterized by abnormal cytoplasmic inclusions of alpha-synuclein protein forming Lewy bodies within neurons 1. The core pathological process involves:

• Progressive loss of dopaminergic neurons in the substantia nigra pars compacta, leading to striatal dopamine deficiency and disruption of the basal ganglia-thalamo-cortical circuit 1, 3
• Clinical symptoms emerge only after approximately 40-50% of dopaminergic neurons have been lost, with an estimated 5-year interval between initial neuronal loss and symptom appearance 4, 1
• Mitochondrial dysfunction, particularly decreased activity of respiratory chain Complex I, represents a key pathophysiological feature 1, 5

Multifactorial Etiology

Aging as the Primary Risk Factor

• Age is the strongest risk factor, with prevalence rising exponentially after age 60, peaking between 60-70 years 4, 2
• Aging impairs cellular pathways that protect dopaminergic neurons, increasing susceptibility to cell death 2
• However, the majority of individuals over age 80 do not develop PD, indicating that aging alone is insufficient to cause disease 2

Genetic Contributions

Genetic factors account for approximately 30% of PD heritability, but pure Mendelian causes represent only 5% of cases 2, 6:

• Familial cases comprise nearly one-third of all PD, with a small subset showing autosomal dominant inheritance 7
• Key genes implicated include SNCA (alpha-synuclein), LRRK2, GBA, parkin, DJ-1, and PINK-1 2, 3, 5
• Common genetic polymorphisms are associated with only small increases in PD risk 2
• Mitochondrial DNA anomalies have also been identified, suggesting mitochondrial genetic contributions 7

Environmental Factors

Environmental exposures contribute to PD risk, though causality remains incompletely established 2, 6:

• Rural residence and pesticide exposure increase PD risk 7, 3
• The synthetic drug MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) can cause parkinsonism, suggesting environmental neurotoxins may play a role 7
• Genes regulating drug and neurotoxin metabolism show modest associations with PD susceptibility 7
• However, the absence of geographic clusters and conjugal cases argues against environmental toxins as a major sole cause 2

Converging Molecular Pathways

The following mechanisms represent common pathways regardless of initial trigger 2, 5:

• Mitochondrial dysfunction and oxidative stress compromise dopaminergic neuronal function 1, 5
• Impaired autophagy leads to accumulation of misfolded proteins 2
• Neuroinflammation contributes to progressive neurodegeneration 2
• Abnormal protein accumulation and phosphorylation, particularly alpha-synuclein, which spreads in a prion-like fashion through brain regions 2, 5

Clinical Implications

Understanding the multifactorial nature of PD is critical because:

• No single factor alone is sufficient to cause PD in most patients 2, 6
• The ultimate cause remains unknown for idiopathic PD, which represents the vast majority of cases 3
• Current therapies only provide symptomatic relief and do not halt dopaminergic neuronal death 5
• Disease-modifying therapies remain elusive due to incomplete understanding of disease initiation mechanisms 3