Biochemistry of Parkinson's Disease

Pathophysiological Basis

Parkinson's disease is classified as a synucleinopathy, characterized by abnormal cytoplasmic inclusions of alpha-synuclein protein in neurons, known as Lewy bodies, which are the hallmark histopathological finding 2
The degeneration of dopaminergic neurons in the substantia nigra pars compacta leads to a deficiency of dopamine in the striatal region, disrupting the normal function of the basal ganglia-thalamo-cortical circuit 1
Symptoms typically manifest after approximately 40-50% of dopaminergic neurons have been lost, with an estimated 5-year interval between initial neuronal loss and symptom appearance 1

Mitochondrial dysfunction, particularly decreased activity of respiratory chain Complex I, is a key feature in Parkinson's disease pathophysiology 3

Several genes have been implicated in Parkinson's disease pathogenesis, including PRRT2, PNKD, SLC2A1, SCN8A, KCNMA1, KCNA19, and DEPDC5 4
PRRT2 is a key negative modulator of Nav1.2 and Nav1.6 channels, and mutations can lead to disturbed cell excitability, presynaptic dysfunction, and abnormal neurotransmitter release 4

Cardinal motor symptoms (bradykinesia, rigidity, resting tremor, and postural instability) result from striatal dopamine deficiency 1
Weight loss is common due to increased energy expenditure from dyskinesias and rigidity 1
Cognitive impairment and dementia, especially in later stages, are important non-motor features related to more widespread neurodegeneration 1

FDG-PET/CT may demonstrate decreased metabolism in temporal, parietal, and occipital lobes as well as the cerebellum in Parkinson's disease 5
Dopamine transporter imaging using SPECT or SPECT/CT can demonstrate loss of dopamine transporter volume in the putamina, manifested as loss of the normal comma shape 5
Loss of the swallow tail sign on susceptibility-weighted MRI is similar to findings in Parkinson's disease 5