Lewy body pathology (LBP) is a hallmark feature found in the brains of individuals with certain progressive neurodegenerative disorders. This pathology is defined by the presence of abnormal protein clumps, known as Lewy bodies, which accumulate inside nerve cells. These microscopic deposits interfere with the normal functioning of neurons, ultimately leading to their damage and death in specific regions of the brain. Understanding the nature of Lewy bodies and the mechanisms by which they cause cellular injury is central to comprehending the origins of debilitating movement and cognitive disorders.
Composition and Structure of Lewy Bodies
The primary component of Lewy bodies is an abundant neuronal protein called alpha-synuclein, encoded by the SNCA gene. Under normal, healthy conditions, this protein is found in the presynaptic terminals of neurons, where it regulates synaptic vesicle trafficking and the release of neurotransmitters. In its pathological state, alpha-synuclein misfolds from its typical soluble form into an insoluble, aggregated structure.
The shape and appearance of Lewy bodies depends on their location within the brain. Classical Lewy bodies, often found in the brainstem, are spherical inclusions with a dense, central core surrounded by a pale, transparent halo. These structures are located within the cytoplasm, where they can displace other cellular components. Cortical Lewy bodies, typically found in the outer layers of the brain, are usually smaller and lack the distinct halo. The misfolded alpha-synuclein within these inclusions forms ordered filamentous structures with a characteristic \(\beta\)-sheet secondary structure.
How Lewy Bodies Form and Propagate
The formation of Lewy bodies is a biological cascade that begins with the misfolding of soluble alpha-synuclein. This misfolded protein then begins to stick to itself, leading to the formation of small, soluble aggregates called oligomers. These oligomers are toxic precursors that eventually mature into insoluble filaments known as fibrils, which are the structural foundation of the visible Lewy body inclusion.
A current hypothesis suggests that Lewy body pathology spreads through the central nervous system in a “prion-like” manner. The misfolded alpha-synuclein acts as a “seed” that is released from one neuron and taken up by a neighboring, healthy neuron. Once inside the recipient cell, the pathological seed then templates the misfolding and aggregation of the cell’s own normal alpha-synuclein, thereby propagating the pathology. This cell-to-cell transmission occurs along anatomically connected pathways, explaining the stereotypical, progressive pattern of pathology observed across different brain regions.
Cellular Damage Caused by Lewy Bodies
The accumulation of alpha-synuclein aggregates, especially the earlier-stage oligomers, inflicts toxic effects that impair a neuron’s ability to function and survive. One major mechanism of damage involves the disruption of the cell’s internal quality control systems, which are responsible for clearing damaged proteins. Specifically, the aggregates impair the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway, leading to a buildup of toxic cellular debris.
Mitochondrial dysfunction is another significant consequence, representing a failure in the cell’s energy supply. Alpha-synuclein interacts with mitochondria, reducing their efficiency and increasing oxidative stress, which creates a toxic environment for the neuron. Aggregates can draw mitochondria toward the Lewy body, causing the organelle to lose integrity and leading to a collapse of cellular energy production. Furthermore, inclusions in the long processes of the neuron, known as Lewy neurites, interfere with axonal transport. This interference blocks the movement of necessary components between the cell body and the synapse, contributing to cell death.
Conditions Associated with Lewy Body Pathology
Lewy body pathology underlies a spectrum of related neurodegenerative disorders, often grouped under the umbrella term Lewy Body Dementia (LBD). The two primary clinical syndromes are Parkinson’s Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB), distinguished mainly by the timing of symptom onset. Parkinson’s Disease (PD) is initially diagnosed as a movement disorder, and PDD is diagnosed when dementia develops years after the onset of motor symptoms.
A diagnosis of DLB is made when cognitive impairment is the first symptom, or when it begins within one year of motor symptom onset. The location of the Lewy bodies largely determines the initial clinical presentation. Pathology concentrated in the brainstem, specifically the substantia nigra, correlates with the motor symptoms of PD, such as tremor and rigidity. The spread of Lewy bodies into the outer, cognitive-processing layers of the brain drives the memory loss, executive dysfunction, and visual hallucinations characteristic of DLB and PDD.
There is also incidental Lewy body disease (iLBD), where Lewy bodies are found at autopsy in individuals who showed no clinical symptoms during life. This suggests it may represent a preclinical or very early stage of the condition.