Parkinson Disease ll: Pathophysiology

Parkinson disease (PD) is a progressive neurodegenerative disorder primarily affecting movement, with additional non-motor features. Its pathophysiology involves complex interactions among genetic susceptibility, environmental exposures, and cellular dysfunction, including dopaminergic neuron loss, protein aggregation, and mitochondrial impairment.

Selective Neurodegeneration

A key feature is the degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to reduced dopamine in the striatum. Normally, dopamine released from SNc neurons modulates striatal medium spiny neurons via D1 and D2 receptors to balance motor activity. In Parkinson disease, reduced dopamine decreases activity in the basal ganglia circuits by decreasing D1 (direct pathway) activity and increasing D2 (indirect pathway) activity, leading to excessive inhibition of thalamocortical signaling and motor symptoms such as tremor, rigidity, and bradykinesia.

Alpha-Synuclein and Lewy Bodies

Misfolded α-synuclein aggregates to form intracellular inclusions known as Lewy bodies. These aggregates disrupt cellular function and may spread between neurons in a prion-like manner, contributing to disease progression.

Mitochondrial Dysfunction and Oxidative Stress

Mitochondrial impairment, including reduced complex I activity and defective mitophagy (linked to PINK1 and Parkin gene mutations), leads to accumulation of damaged mitochondria and increased reactive oxygen species, promoting neuronal death. Environmental toxins such as MPTP and rotenone selectively inhibit mitochondrial function, contributing to PD.

Impaired Protein Clearance

Dysfunction of the ubiquitin–proteasome and autophagy–lysosomal systems results in the accumulation of toxic proteins such as α-synuclein. Mutations in genes like GBA further impair these pathways.

Neuroinflammation and Spread

Activated microglia release cytokines and ROS, worsening injury. The Braak hypothesis proposes that α-synuclein spreads from peripheral sites to the brain. Genetic mutations (SNCA, LRRK2, PINK1, Parkin, DJ-1, GBA) and environmental toxins contribute to interconnected pathological pathways driving progression.