Journal of Alzheimers Disease & Parkinsonism
Open Access

Lewy bodies are abnormal aggregates of protein that develop inside nerve cells and are characteristic of several neurodegenerative diseases, most notably Parkinson’s Disease (PD) and Lewy Body Dementia (LBD). These inclusions in the early 20th century while studying the brains of patients with Parkinson’s disease. The primary protein component of Lewy bodies is alpha synuclein, a protein that, under normal conditions, plays a role in synaptic function and neurotransmitter release. However, in disease states, alpha synuclein misfolds and accumulates into insoluble fibrils, which aggregate to form Lewy bodies.

Lewy bodies are typically found in the cytoplasm of neurons, especially in brain regions associated with movement, cognition, and emotion. In Parkinson’s disease, they are most commonly located in the substantia nigra, a region of the midbrain critical for the production of dopamine. The loss of dopaminergic neurons in this region due to Lewy body accumulation is a major contributor to the motor symptoms characteristic of Parkinson’s, including tremors, rigidity, bradykinesia and postural instability. As the disease progresses, Lewy bodies can also appear in other parts of the brain, contributing to non-motor symptoms such as sleep disturbances, depression and cognitive impairment.

In Lewy body dementia, which includes both Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD), Lewy bodies are more widely distributed throughout the brain, including the cortex. This broader distribution is associated with the hallmark symptoms of LBD, which include progressive cognitive decline, visual hallucinations, fluctuating attention and alertness, and parkinsonian motor features. DLB and PDD are closely related and distinguished primarily by the timing of cognitive versus motor symptom onset. In DLB, cognitive symptoms appear first or simultaneously with motor symptoms, while in PDD, cognitive decline occurs after a clear diagnosis of Parkinson’s disease has been established for at least a year.

The presence of Lewy bodies disrupts normal cellular processes in neurons. Alpha-synuclein, the main constituent of Lewy bodies, is believed to become toxic when it misfolds and aggregates. These aggregates can impair cellular functions by interfering with mitochondrial activity, disrupting protein degradation pathways such as the ubiquitin-proteasome system and autophagy, and affecting synaptic transmission. The progressive accumulation of toxic alpha-synuclein aggregates ultimately leads to neuronal dysfunction and cell death, contributing to the clinical symptoms observed in patients.

The exact cause of alpha-synuclein misfolding and aggregation remains unclear, but both genetic and environmental factors are believed to play roles. Certain mutations in the SNCA gene, which encodes alpha-synuclein, have been linked to familial forms of Parkinson’s disease and result in an increased propensity for the protein to aggregate. Additionally, mutations in other genes and have been associated with increased risk of Lewy body-associated diseases. Environmental exposures, oxidative stress, and neuroinflammation may also contribute to the pathological cascade that leads to Lewy body formation.

Lewy bodies are abnormal protein aggregates primarily composed of alpha-synuclein and are central to the pathology of several neurodegenerative diseases, especially Parkinson’s disease and Lewy body dementia. Their presence reflects a cascade of cellular dysfunctions that result in the progressive loss of neuronal function and clinical symptoms. Understanding the biology of Lewy bodies holds the key to advancing both diagnosis and treatment of these challenging conditions. The complexity of Lewy body diseases underscores the need for a multidisciplinary approach to care and continued investment in research to improve outcomes for those affected.