Studies conducted on mice and human brains by neurologists at Georgetown University Medical Center (GUMC) have revealed one of the factors that lead to Parkinson’s Disease (PD), the accumulation of alpha-synuclein proteins in the brain’s motor area. Clusters of these proteins — known as Lewy bodies — cannot be cleared through natural processes and are a hallmark of PD.
The team at GUMC has found that one reason for the development of Lewy bodies is because a molecule known as USP13 removes all the ‘tags’ that mark the accumulated protein for destruction. By inhibiting USP13 molecules in mouse models, the researchers both eliminated existing Lewy bodies and prevented them from building up again.
“This study provides novel evidence that USP13 affects development and clearance of Lewy body protein clumps,” says the study’s lead investigator, Assistant Professor of Neurology Xiaoguang Liu. In a statement, she suggested that targeting USP13 may have a therapeutic effect in PD and similar forms of neurodegeneration.
The study was initiated with post-mortem examinations of individuals who had donated their brains for scientific research. This included 11 PD patients and nine individuals without the disease. When autopsies occured within four to 12 hours after death, USP13 levels were found to be significantly elevated in PD patients. This was the first time overexpression of USP13 was found in the brains of PD patients post mortem. Subsequent studies of mouse models revealed that reducing USP13 levels protected the mice against alpha-synuclein accumulation in the brain’s motor area, resulting in significant improvement in motor function.
“To our knowledge, these data are the first to elucidate the role of USP13 in neurodegeneration,” says Liu. This suggests that other neurodegenerative disorders that feature protein clumps, such as Alzheimer’s disease, may have a similar pathology.
“Clearance of neurotoxic proteins, including alpha-synuclein, may depend on the balance between ubiquitination and deubiquitination,” adds Liu.