What is the cause of Parkinson's disease?

Cause of Parkinson's Disease

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

Primary Pathophysiological Mechanism

The fundamental pathology involves selective loss of dopaminergic neurons in the substantia nigra, which project to the striatum and are essential for motor control 1, 3. The disease manifests clinically only after approximately 40-50% of these dopaminergic neurons have been lost, typically occurring over a 5-year interval before symptoms appear 1, 2.

Molecular Hallmark: Alpha-Synucleinopathy

• Parkinson's disease is classified as a synucleinopathy, characterized by abnormal cytoplasmic accumulation of misfolded alpha-synuclein protein forming Lewy bodies within neurons 2, 4
• These Lewy bodies are composed predominantly of alpha-synuclein and ubiquitin, representing the pathological hallmark of the disease 1, 5
• The misfolded alpha-synuclein spreads through the brain in a prion-like fashion, initially affecting the medulla oblongata, pontine tegmentum, and olfactory system, then progressing to the substantia nigra and eventually cortical regions 1, 6

Etiological Factors

Aging as the Primary Risk Factor

• Age is the strongest risk factor, with disease prevalence rising exponentially after age 60, affecting approximately 1% of the population over 60 years 7
• Peak age of onset occurs between 60-70 years 1
• However, aging alone is insufficient to cause disease, as the majority of individuals over 80 do not develop Parkinson's disease 6

Genetic Contributions

• Genetic factors account for approximately 5-10% of cases, with most cases being sporadic of unknown etiology 7, 5
• Heritability is estimated at around 30% 6
• Key genes implicated include: SNCA (encoding alpha-synuclein), LRRK2, parkin, DJ-1, PINK-1, GBA, PRRT2, PNKD, SLC2A1, SCN8A, KCNMA1, KCNA19, and DEPDC5 2, 3, 6
• Rare monogenic mutations show autosomal dominant inheritance with incomplete penetrance (60-90%), but collectively account for only 5% of all cases 7, 5

Environmental Factors

• Environmental exposures are associated with increased risk, including pesticide exposure and certain environmental chemicals (such as synthetic heroin/MPTP) 4, 6
• The causality of most environmental factors remains inconclusive, with concerns about reverse causality and recall bias 6
• The absence of geographic clusters and conjugal cases argues against environmental toxins as a major sole cause 6

Converging Pathogenic Mechanisms

Cellular Dysfunction Pathways

• Mitochondrial dysfunction, particularly decreased activity of respiratory chain Complex I, is a key pathophysiological feature 2, 3
• Impaired autophagy leads to accumulation of damaged proteins and organelles 6
• Oxidative stress and damage compromise dopaminergic neuronal function 3, 6
• Abnormal protein accumulation and phosphorylation disrupt normal cellular processes 3
• Neuroinflammation contributes to progressive neurodegeneration 6

Circuit-Level Dysfunction

• Disruption of the basal ganglia-thalamo-cortical circuit underlies the motor manifestations of the disease 2
• Dopamine deficiency in the striatum impairs the normal facilitation of voluntary movements 7

Clinical Implications

The multifactorial nature means that aging, genetics, and environmental factors each alone are rarely sufficient to cause Parkinson's disease in most patients 6. This explains why:

• Not all elderly individuals develop the disease despite age-related neuronal vulnerability
• Not all individuals with genetic risk variants develop clinical disease
• Environmental exposures alone do not consistently produce parkinsonism in exposed populations

Important Caveat

The ultimate cause(s) of sporadic Parkinson's disease remain unknown in the majority of cases 4, 5. Current understanding suggests that individual susceptibility results from the convergence of multiple risk factors rather than a single causative agent, making prevention and disease-modifying therapy challenging to develop 3, 4.