Researchers at Georgetown University Medical Center discovered that the protease USP13 (ubiquitin-specific peptidase 13) plays a role in the accumulation of toxic alpha-synuclein aggregates that characterize Parkinson’s disease .
Ubiquitin specific proteases (USPs) are de-ubiquitinases that control the protein ubiquitination cycle. The role of de-ubiquitinases is poorly understood in neurodegenerative diseases. We found that USP13 is overexpressed in the post-mortem Parkinson’s disease (PD) brain. We investigated whether changes in USP13 levels can affect two molecules, parkin and alpha-synuclein, that are implicated in PD pathogenesis. Parkin is an E3 ubiquitin ligase that is regulated by ubiquitination and targets certain proteins for degradation, and alpha-synuclein may be ubiquitinated and recycled in the normal brain. We found that USP13 independently regulates parkin and alpha-synuclein ubiquitination in models of alpha-synucleinopathies. USP13 shRNA knockdown increases alpha-synuclein ubiquitination and clearance in a parkin-independent manner. Furthermore, USP13 over-expression counteracts the effects of a tyrosine kinase inhibitor, Nilotinib, while USP13 knockdown facilitates Nilotinib effects on alpha-synuclein clearance, suggesting that alpha-synuclein ubiquitination is important for its clearance. These studies provide novel evidence of USP13 effects on parkin and alpha-synuclein metabolism and suggest that USP13 is a potential therapeutic target in the alpha-synucleinopathies.
Parkinson’s disease and alpha-synuclein
Parkinson’s disease is a neurodegenerative condition that affects the brain’s motor control area, leading to slowness of movement, shaking, rigidity, and, in some cases, dementia as well. The accumulation of alpha-synuclein aggregates known as Lewy bodies, typical of the disease, gradually destroys dopaminergic neurons in an area of the brain known as the substantia nigra. The inability of the body to break down these protein clumps is what leads to their buildup and eventually the emergence of the pathology.
The team led by Dr. Xiaoguang Liu found that USP13 seems to be a culprit in alpha-synuclein buildup.
Proteins that need to be broken down are typically “marked” for destruction when they bind with marker molecules that signal proteases to degrade them. Ubiquitin, a protein owing its name to its presence in nearly all eukaryotic species, is one of these marker proteins tagging alpha-synuclein for destruction. If the tag happens to be removed, alpha-synuclein clumps start to form and are not disposed of. USP13 is known to cause alpha-synuclein to be de-ubiquitinated—that is, the ubiquitin “tag” is removed from it—or even impair the ubiquitination process in the first place by reducing the efficacy of another protein—known as parkin—involved in it.
The research was conducted both on human brains post-mortem and on mice. The scientists examined the brains of eleven PD patients and 9 PD-free controls; they discovered that USP13 was overexpressed in the brains of Parkinson’s patients and not the controls. This led the scientists to suspect that excess USP13 might be behind the accumulation of alpha-synuclein in dopaminergic neurons.
The researchers then moved on to a mouse model of PD, and they discovered that knocking out the USP13 gene encoding the USP13 protein not only increased alpha-synuclein ubiquitination and clearance, it also prevented dopaminergic-neuron death, ultimately improving the motor control of the mice. In the study, the researchers also observed that nilotinib, a drug previously shown to improve alpha-synuclein clearance, was more effective on USP13 knockout mice, suggesting that USP13 overexpression interferes with the drug.
It is the researchers’ opinion that USP13 might be a viable therapeutic target to treat Parkinson’s disease. Its inhibition may help activate parkin and counteract the de-ubiquitination of alpha-synuclein, allowing the breakdown of Lewy bodies. Moving forward, the researchers plan to develop a small-molecule inhibition of USP13 which, when used in combination with nilotinib, might lead to better aggregate clearance not only in Parkinson’s disease but also in other neurodegenerative conditions characterized by protein aggregation, such as Alzheimer’s disease.
 Liu, X., Hebron, M., Shi, W., Lonskaya, I., & Moussa, C. E.-H. (2018). Ubiquitin specific protease-13 independently regulates parkin ubiquitination and alpha-synuclein clearance in alpha-synucleinopathies. Human Molecular Genetics.