The pathophysiology of Parkinson's disease is death of dopaminergic neurons as a result of changes in biological activity in the brain with respect to Parkinson's disease (PD). There are several proposed mechanisms for neuronal death in PD; however, not all of them are well understood. Five proposed major mechanisms for neuronal death in Parkinson's Disease include protein aggregation in Lewy bodies, disruption of autophagy, changes in cell metabolism or mitochondrial function, neuroinflammation, and blood–brain barrier (BBB) breakdown resulting in vascular leakiness.
Protein aggregation
The first major proposed cause of neuronal death in Parkinson's disease is the bundling, or oligomerization, of proteins. The protein alpha-synuclein has increased presence in the brains of Parkinson's Disease patients and, as α-synuclein is insoluble, it aggregates to form Lewy bodies (shown to left) in neurons. Traditionally, Lewy bodies were thought to be the main cause of cell death in Parkinson's disease; however, more recent studies suggest that Lewy bodies lead to other effects that cause cell death. Regardless, Lewy bodies are widely recognized as a pathological marker of Parkinson's disease.
Lewy bodies first appear in the olfactory bulb, medulla oblongata, and pontine tegmentum; patients at this stage are asymptomatic. As the disease progresses, Lewy bodies develop in the substantia nigra, areas of the midbrain and basal forebrain, and in the neocortex.
This mechanism is substantiated by the facts that α-synuclein lacks toxicity when unable to form aggregates; that heat-shock proteins, which assist in refolding proteins susceptible to aggregation, beneficially affect PD when overexpressed; and that reagents which neutralize aggregated species protect neurons in cellular models of α-synuclein overexpression.
Alpha-synuclein appears to be a key link between reduced DNA repair and Parkinson’s disease. Alpha-synuclein activates ATM (ataxia-telangiectasia mutated), a major DNA damage repair signaling kinase. Alpha-synuclein binds to breaks in double-stranded DNA and facilitates the DNA repair process of non-homologous end joining. It was suggested that cytoplasmic aggregation of alpha-synuclein to form Lewy bodies reduces its nuclear levels leading to decreased DNA repair, increased DNA double-strand breaks and increased programmed cell death of neurons.
Autophagy disruption
The second major proposed mechanism for neuronal death in Parkinson's disease, autophagy, is a mechanism by which inner components of the cell are broken down and recycled for use. Autophagy has been shown to play a role in brain health, helping to regulate cellular function. Disruption of the autophagy mechanism can lead to several different types of diseases like Parkinson's disease.
Autophagy dysfunction in Parkinson's disease has also been shown to lead to dysregulated mitochondria degradation.
Changes in cell metabolism
The third major proposed cause of cell death in Parkinson's disease involves the energy-generating mitochondrion organelle. In Parkinson's disease, mitochondrial function is disrupted, inhibiting energy production and resulting in death.
The mechanism behind mitochondrial dysfunction in Parkinson's disease is hypothesized to be centered in the PINK1 and Parkin complex, having this been shown to drive autophagy of mitochondria (also known as mitophagy). PINK1 is a protein normally transported into the mitochondrion, but can also accumulate on the surface of impaired mitochondria. Accumulated PINK1 then recruits Parkin; Parkin initiates the breakdown of dysfunctional mitochondria, a mechanism that acts as a "quality control". In Parkinson's disease, the genes coding PINK1 and Parkin are thought to be mutated so as to impair the ability of these proteins to breakdown dysfunctional mitochondria, leading to abnormal mitochondrial function and morphology, and eventually cell death. Mitochondrial DNA (mtDNA) mutations have also been shown to accumulate with age indicating that susceptibility to this mechanism of neuronal death increases with age.
Another mitochondrial-related mechanism for cell death in Parkinson's disease is the generation of reactive oxygen species (ROS). ROS are highly reactive molecules that contain oxygen and can disrupt functions within the mitochondria and the rest of the cell. With increasing age, mitochondria lose their ability to remove ROS yet still maintain their production of ROS, causing an increase in net production of ROS and eventually cell death.