Pharmacological inhibition of O-GlcNAcase reduces pS129-α-synuclein positive aggregates in the substantia nigra of mThy1-hSNCA mice.

BackgroundThe aggregation and spread of α-synuclein within brain are associated with the loss of dopaminergic neurons and the formation of Lewy bodies as seen in Parkinson's disease. Blocking the initiation of α-synuclein aggregation, or the spread of such aggregates, may offer disease-modifying approaches to slow disease progression. Previous studies have demonstrated that modification of aggregation prone proteins, including α-synuclein, with O-linked β-N-acetylglucosamine (O-GlcNAc) reduces their aggregation. Small molecule inhibitors of the enzyme O-GlcNAcase (OGA), which removes O-GlcNAc from proteins, confers neuroprotective benefits in various preclinical disease models of Alzheimer's and Parkinson's diseases.ObjectiveThis study investigates the effects of long-term pharmacological enhancement of O-GlcNAcylation in a transgenic mouse model of Parkinson's disease overexpressing human α-synuclein.MethodsThiamet-G was orally administered to mThy1-hSNCA and wild-type (WT) mice for ten months. Behavioral assessments were conducted to examine changes in locomotion and cognition. Histological analyses were performed to analyze α-synuclein aggregates and dopaminergic neurons in brain sections. Immunoblot and ELISA analyses were performed to analyze O-GlcNAc and soluble α-synuclein using brain lysates, respectively.ResultsThiamet-G increased the level of O-GlcNAc in the brain of both mThy1-hSNCA and WT mice. The levels of total α-synuclein in the brain were unaltered. However, Thiamet-G strongly attenuated the deposition of pS129-immunoreactive α-synuclein aggregates within the substantia nigra, prior to observable neurodegeneration. Thiamet-G also protected against locomotor decline.ConclusionsThese results support OGA inhibition as a therapeutic approach to block the pathological formation of toxic α-synuclein as a disease-modifying treatment against Parkinson's disease. Currently there are no medicines that can slow or halt the progression of Parkinson's disease. Research suggests that clumping of the neuronal protein α-synuclein within the brain is toxic and drives the advance of the disease. Slowing the clumping together of α-synuclein therefore offers a possible approach to develop a treatment to slow the disease. To test this idea, we treated mice for ten months with a compound that increases modification of proteins with a sugar known as O-GlcNAc. This molecule has been shown to be safe and well-tolerated with protective benefits in several disease mouse models. Using mice that express human α-synuclein and develop Parkinson's disease, we tested the effects of the treatment on motor control and cognition by getting these mice to perform various tasks. After treatment, we studied brain tissues for changes in the clumping of α-synuclein and other markers in the brain. We found the molecule reliably increased protein O-GlcNAc in the brain. We also found that the treatment significantly reduced the formation of toxic α-synuclein in the brain. Moreover, we observed the treatment helped preserve locomotion. These results support the idea that increasing protein O-GlcNAc in brain can slow the formation of toxic α-synuclein and may be an effective approach to slow the progression of Parkinson's disease.