Lewy bodies are abnormal protein clumps primarily composed of alpha-synuclein, found in the brains of individuals with neurodegenerative disorders. Their accumulation is a key feature in conditions like Parkinson’s disease and Lewy body dementia.
The Alpha-Synuclein Protein
Alpha-synuclein is a small protein abundant in the brain, especially at presynaptic terminals at neuron tips. These terminals release neurotransmitters, enabling neuronal communication. In its healthy state, alpha-synuclein is an intrinsically disordered protein, lacking a fixed three-dimensional structure and adopting various shapes.
It plays a role in synaptic vesicle trafficking, involving the movement and recycling of neurotransmitter-storing sacs. It also influences neurotransmitter release and contributes to synaptic plasticity, including synaptic strengthening or weakening. Alpha-synuclein is crucial for neuronal communication and expressed throughout the brain. Its normal functions include involvement in neurotransmitter synthesis, calcium regulation, and gene expression.
How Lewy Bodies Form
Lewy bodies develop when alpha-synuclein proteins misfold and aggregate. Normally, cells fold proteins precisely and have mechanisms to remove misfolded ones. However, genetic mutations or aging can impair these systems, allowing alpha-synuclein to adopt incorrect, unfixable shapes.
Misfolded alpha-synuclein then clumps, transitioning from individual units (monomers) into small clusters (oligomers), then fibrils, eventually forming dense, insoluble Lewy bodies. These aggregates, typically 5 to 25 micrometers in diameter, are found within neuron cytoplasm and are largely alpha-synuclein, with other proteins and cellular components. Post-translational modifications, like phosphorylation, are also associated with aggregation and are a pathological hallmark.
The formation of these aggregates disrupts normal cellular processes, including material transport, mitochondrial function, and waste breakdown. This disruption impairs neuronal function and contributes to neuronal degeneration. Aggregation is influenced by alpha-synuclein concentration, with higher levels promoting fibril formation.
Conditions Linked to Lewy Bodies
Lewy bodies are a defining feature of several neurodegenerative diseases, collectively known as synucleinopathies. The most prominent are Parkinson’s disease (PD) and Lewy body dementia (LBD), which encompasses Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD). The location and spread of Lewy bodies within the brain contribute to diverse patient symptoms.
In Parkinson’s disease, Lewy bodies primarily affect neurons in the substantia nigra, a brain region involved in movement control. Their degeneration leads to characteristic motor symptoms such as tremors, rigidity, and slowness of movement. In contrast, Dementia with Lewy Bodies (DLB) involves a more widespread distribution of Lewy bodies, particularly in cortical regions. This broader pathology contributes to cognitive fluctuations, recurrent visual hallucinations, and attention/executive function problems, often preceding or occurring early in the disease.
Parkinson’s Disease Dementia (PDD) occurs when cognitive decline develops significantly later than the onset of motor symptoms in individuals with Parkinson’s disease. While both DLB and PDD involve Lewy bodies, the timing of cognitive versus motor symptom onset helps distinguish them. Lewy bodies can also be found as co-pathologies in other neurodegenerative conditions, such as Alzheimer’s disease.
Research and Therapeutic Approaches
Research aims to understand alpha-synuclein aggregates to develop effective interventions. Diagnostic advancements focus on earlier detection of alpha-synuclein pathology, including identifying biomarkers in cerebrospinal fluid or skin biopsies to diagnose conditions before significant neuronal damage.
Some therapeutic approaches focus on reducing alpha-synuclein production or preventing its misfolding and aggregation into toxic forms. Another strategy involves clearing existing alpha-synuclein aggregates from the brain, potentially using immunotherapies that target the aggregated protein or small molecules designed to break them down.
Protecting neurons from toxic alpha-synuclein aggregates is also a research area. This includes investigating ways to support neuronal health and function despite the presence of pathology. Ongoing clinical trials and research initiatives offer hope for future treatments that could slow, halt, or even prevent the progression of diseases linked to Lewy bodies.