Copathologies in neurodegenerative disease

Cytoplasmic deposition of alpha-synuclein aggregates is a common pathological feature of many neurodegenerative synucleinopathies, including Parkinson's disease and dementia with Lewy bodies. This suggests a causative role of alpha-synuclein in these diseases.

Importantly, a particular pathology is associated with a specific disease, such as Lewy bodies with Parkinson's disease and dementia with Lewy bodies or amyloid plaques and tau tangles with Alzheimer's disease, the reality is that many patients' brains harbor multiple pathologies. For example, many patients with Alzheimer's disease have comorbid alpha-synuclein pathology (Lewy bodies) and tau tangles. In patients with dementia with Lewy bodies, almost all brains carry both alpha-synuclein pathology and amyloid-beta pathology. TDP-43 is another protein that was initially linked to amyotrophic lateral sclerosis, but it also can be found to accumulate in brains affected by Alzheimer's disease and Parkinson's disease.

The Neurobiology of Parkinson's Disease and Related Disorders Lab and others are deciphering the role of aggregation and copathologies in disease. Researchers in the lab use proximity proteomics, proximity ligation assays, and cell and animal models to investigate how the different copathologies influence each other.

Discovering what forms of alpha-synuclein protein are toxic to neurons and how other toxic proteins influence this can help the research team develop therapeutic strategies to target specific forms of alpha-synuclein and stop cell death.