Dementia with Lewy bodies (DLB) is a neurodegenerative disease affecting over 1 million in the United States alone. Although typically diagnosed in those 50 and older, DLB can also affect younger people. The NIH estimates it to be the third most common form of dementia, after Alzheimer’s disease and vascular disease. Symptoms include confusion, changes in reasoning, motor problems, and difficulty processing sensory information. These symptoms make it particularly difficult to diagnose the disease as they are similar to those of Parkinson’s and Alzheimer’s disease. This, in turn, leads to issues in discovering and treating the disease early on. Similar to other forms of dementia, there is currently no cure for the DLB, so early diagnosis is critical in slowing progression of the disease. Current treatments aim to reduce individual symptoms rather than the underlying cause of the disease. An absence of cure is not for lack of trying; formulating treatments for DLB is rendered challenging by how little is actually known on why/how the disease forms and the role of a-synuclein.
The name dementia with Lewy bodies comes from the characteristic deposits of a-synuclein protein in the brains of patients affected. These deposits aggregate into what are called Lewy bodies, named after Fritz Heinrich Lewy–the scientist who discovered them. Relatively little is known about a-synuclein, although researchers speculate that it functions in maintaining a supply of synaptic vesicles and regulates release of the neurotransmitter dopamine, which controls involuntary and voluntary movement. The molecular mechanism behind how a-synuclein forms aggregates is currently under debate. Some scientists believe that in its native form, a-synuclein exists as a monomer, while others believe it to exist as a tetramer. In a monomer model, a-synuclein is proposed to undergo structural change, causing it to aggregate and become insoluble. In the tetramer model, it’s proposed to be resistant to aggregation in this form and it is disruptions to the structure from post-translational modifications that render the protein more likely to aggregate. These post-translational modifications include phosphorylation on serine residue S129, with higher levels of phosphorylation correlated to more aggregates, and are proposed to be involved in both models.
Although the method of propagation of a-synuclein is still unclear, the protein is proposed to act in a prion fashion, meaning it becomes self-propagating. Research indicates that, in Lewy body form, aggregated a-synuclein has little propagating ability; however, oligomeric forms of a-synuclein in both phosphorylated and un-phosphorylated state exhibit seeding ability. This suggests that it is oligomeric a-synuclein that is responsible for the prion behavior rather than mature a-synuclein fibrils (see graphical abstract).
The pathways through which a-synuclein is degraded are still subject to debate, though research indicates that proteases, enzymes that work to break down proteins, play a key role in a-synuclein degradation. Kallikrein-6 (KLK6) and calpain-1 (CALN1) are the two main proteases that break down a-synuclein. KLK6 is found abundantly in the brain and is known to cleave monomeric a-synuclein. This process is proposed to reduce aggregation by reducing levels of a-synuclein all-together. CALN1 activity cleaves both monomeric and fibrillary forms of a-synuclein. There is some debate as to whether the cleavage of fibrillary a-synuclein might not increase aggregation; however, a recent study found that reduction of CALN1 lead to increase in phosphorylated serine-129. Researchers propose that a reduction in these enzymes contributes to the accumulation of a-synuclein in dementia with Lewy bodies. Post-mortem analysis reveals a decrease in the concentrations of these proteases in brains of patients with dementia. Delivery of kallikrein-6 to the brain of a mouse model with Lewy bodies was found to reduce the accumulation of a-synuclein and improve neuronal synapse function, indicating that these proteases may constitute possible leads in treating dementia with Lewy bodies.
While most research tends to focus on a-synuclein proteases, other components exist that are involved in DLB development, such as the mitochondria. Staining experiments between control and DLB patient reveal differences in mitochondrial markers, indicating marked mitochondrial loss in those with the disease. Further studies reveal that mitochondria are drawn to early sites of a-synuclein aggregation and as they are incorporated they lose function. Thus, some propose that cell death in DLB is caused by this mitochondrial loss.
Further research is required to better understand the disease. There is still much about DLB that is unclear and needs to be elucidated in order to generate successful treatments. Notably the controversy regarding native conformation and the mechanism behind a-synuclein aggregation require additional research.