What is the biochemistry of Parkinson's disease?

Biochemistry of Parkinson's Disease

Parkinson's disease is primarily characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to dopamine deficiency in the striatum, which manifests after approximately 40-50% of these neurons have been lost. 1, 2

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 3
• 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, 2
• 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

Molecular Mechanisms of Neurodegeneration

• Alpha-synuclein mutations can impair neurotransmitter storage, potentially leading to cytoplasmic accumulation of dopamine, which is unstable and can promote oxidative stress 4
• Mitochondrial dysfunction, particularly decreased activity of respiratory chain Complex I, is a key feature in Parkinson's disease pathophysiology 5, 6
• Proteasome dysfunction may contribute to neurodegeneration, especially in inherited forms of the disease caused by mutations in genes encoding Parkin, alpha-synuclein, and UCHL-1 proteins 6
• Oxidative stress from reactive oxygen species and impaired detoxification mechanisms contribute to dopaminergic neuron damage 6, 7

Cell Death Mechanisms

• Dopaminergic neurons in Parkinson's disease exhibit characteristics of both apoptosis (programmed cell death) and autophagic degeneration 7
• Apoptosis involves activation of specific proteases called caspases, which execute the controlled cell death process 6
• Three populations of dopaminergic neurons coexist in the substantia nigra of Parkinson's disease patients: spared senescent neurons, sick neurons with metabolic abnormalities, and neurons in final stages of apoptotic cell death 6
• Neuroinflammation involving activated glial cells (astrocytes and microglia) may perpetuate or amplify neuronal damage through proinflammatory cytokines and nitric oxide 6

Neurotransmitter Systems

• While dopamine deficiency is the primary neurochemical abnormality, other monoamine systems (norepinephrine and serotonin) are also affected, contributing to non-motor symptoms 8
• Levodopa, the metabolic precursor of dopamine, crosses the blood-brain barrier and is converted to dopamine in the brain, which is the basis for symptomatic treatment 9
• Carbidopa inhibits the peripheral decarboxylation of levodopa, preventing its conversion to dopamine outside the brain, thereby increasing levodopa availability to the central nervous system 9
• Vesicular monoamine transporter (VMAT2) dysfunction can lead to impaired storage of monoamines, contributing to both motor and non-motor symptoms 8

Genetic Factors

• Several genes have been implicated in Parkinson's disease pathogenesis, including PRRT2, PNKD, SLC2A1, SCN8A, KCNMA1, KCNA19, and DEPDC5 5
• 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 5
• Mutations in genes encoding alpha-synuclein, Parkin, and UCHL-1 can lead to dysfunction of the proteasome system, resulting in accumulation of abnormal proteins toxic to dopaminergic neurons 6

Clinical Implications of Biochemical Changes

• Cardinal motor symptoms (bradykinesia, rigidity, resting tremor, and postural instability) result from striatal dopamine deficiency 1, 2
• Non-motor symptoms (olfactory dysfunction, gastrointestinal issues, sleep disturbances, anxiety, and depression) may result from dysfunction in multiple neurotransmitter systems beyond dopamine 8
• 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

Diagnostic Biomarkers

• 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