Pathophysiology

Genetics of PD

• Genetic Contribution: Genetic forms of PD account for approximately 5-10% of all cases. The likelihood of a genetic basis increases with early onset of the disease, especially in individuals with Young-Onset Parkinson’s Disease (YOPD). For those with disease onset before 30 years of age, the proportion of genetically defined cases rises to over 40%.
• Major Genes Identified: The major genes identified and proven to be causal in PD include Parkin (PARK2), Leucine-rich repeat kinase 2 (LRRK2/PARK8), Alpha-synuclein (SNCA-PARK1/PARK4), PTEN induced putative kinase 1 (PINK1/PARK6), DJ1 (PARK7), ubiquitin C-terminal hydrolase like 1 (UCH-L1), and ATPase type 13A2 (ATP13A2).

Neurodegeneration and Lewy Bodies

• Dopaminergic Neuron Loss: The pathophysiology of PD primarily involves the loss or degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc).
• Lewy Bodies: Accumulation of Lewy bodies, which are abnormal intracellular aggregates containing proteins like alpha-synuclein and ubiquitin, is a hallmark of PD. Approximately 60-70% of neurons in the SNpc are lost before symptoms appear.
• Disease Progression: The pathogenic process starts in the cholinergic and monoaminergic brainstem neurons and the olfactory system, eventually involving limbic and neocortical brain regions as the disease progresses. The loss of dopaminergic neurons, initially confined to the SNpc, becomes more widespread in end-stage disease.

Motor Circuit Changes

• Striatal Impairment: Selective loss of dopaminergic neurons in the striatum leads to impaired motor control in PD patients.
• Motor Circuitry: The motor circuit of PD consists of corticostriatal projections from various motor cortex areas terminating on the dendrites of the striatal medium spiny neurons.
• Direct and Indirect Pathways: The direct pathway involves a monosynaptic connection between medium spiny neurons expressing dopamine D1 receptors and GABAergic neurons in the globus pallidus internus (Gpi) and the substantia nigra pars reticulata (SNpr). The indirect pathway, originating from medium spiny neurons expressing D2 receptors, projects to the globus pallidus externus (Gpe) and reaches the Gpi via the subthalamic nucleus (STN) as a glutamatergic relay.
• Dopamine’s Role in Basal Ganglia Activity: Dopaminergic tone in the striatum regulates GABAergic output activity of the basal ganglia. In PD, there is a reduction in D1 mediated direct pathway activity and an increase in D2 mediated indirect pathway activity, resulting in increased firing rates of basal ganglia output neurons (GABA), which leads to over-inhibition of downstream thalamocortical and brainstem areas.