Alpha-Synuclein Aggregates (Lewy Bodies) | What Are These Brain Clumps and How Do They Affect Us?

Alpha-synuclein is a protein that is abundant in the human brain, found specifically at the presynaptic terminals of neurons. Presynaptic terminals are the endings of nerve cells (neurons) that release chemical messengers, called neurotransmitters, to communicate with other neurons. In its healthy, native state, alpha-synuclein is thought to be involved in regulating the release of these neurotransmitters. For example, it helps to control the supply of synaptic vesicles, which are small sacs that store neurotransmitters. Proper function of alpha-synuclein is essential for synaptic plasticity, the ability of synapses to strengthen or weaken over time, which is a fundamental process for learning and memory. The protein normally exists in a soluble, unfolded state, meaning it does not have a fixed three-dimensional structure. This flexibility allows it to interact with other molecules and membranes within the cell, performing its duties without causing harm. It is only when this protein changes its shape and begins to clump together that it becomes associated with neurodegenerative diseases.

The transition from a harmless, functional protein to a toxic aggregate is a central event in the pathology of diseases like Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). This process begins when individual alpha-synuclein proteins, or monomers, misfold into an abnormal shape. These misfolded monomers are "sticky" and start to clump together, first forming small, soluble clusters called oligomers, and then larger, insoluble filaments known as fibrils. Over time, these fibrils continue to accumulate inside the neuron, eventually forming the dense, spherical inclusions known as Lewy bodies. The exact trigger for this misfolding is not fully understood but is believed to involve a combination of genetic predisposition and environmental factors. Once formed, these Lewy bodies disrupt normal cellular activities and are considered a defining pathological hallmark of a class of neurodegenerative disorders called synucleinopathies.

Lewy bodies and their precursor aggregates, oligomers, exert their toxicity through multiple mechanisms. They interfere with critical cellular machinery, leading to widespread dysfunction and eventual cell death. One major target is the mitochondrion, the cell's powerhouse; aggregates can impair mitochondrial function, leading to an energy deficit and increased oxidative stress. They also disrupt the ubiquitin-proteasome system and autophagy, which are the cell's primary waste disposal and recycling systems. When these systems are clogged by protein clumps, the cell cannot clear out damaged components, leading to a buildup of toxic materials. Furthermore, aggregates can interfere with axonal transport, the process of moving essential molecules along the neuron's long axon, effectively starving the synapses of necessary supplies and leading to a breakdown in neural communication.

No, the distribution of Lewy bodies varies depending on the specific disorder, and this distribution pattern directly correlates with the clinical symptoms observed in the patient. In Parkinson's disease, the pathology typically begins in the brainstem, specifically in a region called the substantia nigra. The neurons in this area produce dopamine and are crucial for controlling movement. As these cells are damaged and die, the classic motor symptoms of PD, such as tremor, rigidity, and slowness of movement, emerge. In Dementia with Lewy Bodies (DLB), the aggregates are much more widely distributed and are found throughout the cerebral cortex, the outer layer of the brain responsible for higher-level thinking. This widespread cortical pathology is why DLB is characterized by prominent cognitive symptoms, such as fluctuating attention, recurrent visual hallucinations, and impaired executive function, in addition to motor deficits.

Although both DLB and Parkinson's disease are caused by the same underlying pathology—the aggregation of alpha-synuclein into Lewy bodies—they are distinguished clinically based on the timing of symptom onset. This distinction is often referred to as the "one-year rule." In Parkinson's disease, the initial symptoms are predominantly motor-related. Significant cognitive decline or dementia typically appears much later in the disease course, if at all, and a diagnosis of Parkinson's disease dementia (PDD) is given only if dementia begins more than one year after the onset of motor symptoms. Conversely, in DLB, the cognitive and psychiatric symptoms are the presenting features. According to diagnostic criteria, dementia must occur before, concurrently with, or within one year of the onset of parkinsonian motor symptoms for a diagnosis of DLB to be made. This rule highlights that while the molecular cause is the same, the initial location and progression of the pathology in the brain create two distinct clinical syndromes. DLB pathology is widespread in the cortex from early on, while PD pathology starts in the brainstem and ascends to cortical areas over a much longer period.