UBR5 Protein May Reduce Neurodegeneration in Huntington's Disease

August 23, 2018

Investigators have discovered a mechanism that could reduce the toxic aggregation of huntingtin protein, which is responsible for neurodegeneration in patients with Huntington’s disease.

A mechanism capable of blocking the accumulation of toxin protein aggregates responsible for neurodegeneration in Huntington’s disease has been identified by investigators at the University of Cologne’s Cluster of Excellence for Aging Research (CECAD).

By examining the underlying mechanisms of the rare disease, investigators were able to identify a protein, referred to as UBR5, a ubiquitin ligase which serves as a protective mechanism for cells and encourages the degradation of mutant huntingtin.

For the study, published in the journal Nature Communications, the investigative team utilized induced pluripotent stem cells (iPSC) derived from patients with Huntington’s disease, which can undergo unlimited self-renewal while maintaining their ability to differentiate into any cell type, such as neurons; iPSCs exhibit a striking ability to avoid the toxic aggregation of polyQ-expanded huntingtin (HTT), the mutant protein underlying Huntington’s disease. Although iPSCs express the mutant gene responsible for the disease, no aggregates were found.

For their study, the investigators screened immoral iPSCs from patients and derived neurons to assess any differences in their ability to avoid aggregation of mutant HTT. The investigators found that huntingtin can be degraded by the proteasome, a cellular disposal system. When it comes to neurons, the system is defective and leads to aggregation of mutant HTT.

iPSCs were observed to exhibit high levels of UBR5; the team found that overexpression of UBR5 accelerates the degradation of huntingtin in cells.

Knowing this, the team decided to further evaluate on the role of UBR5 in the regulation of mutant HTT. When investigators reduced the levels of UBR5 in iPSCs, they observed an increase in aggregated proteins, what authors of the paper described to be a “striking” discovery. When they tested to see if UBR5 controls mutant HTT aggregation in invertebrate models, they found that dysregulation of UBR5 significantly hastened aggregation and neurotoxicity.

“Besides HTT levels, intrinsic enhanced UBR5 expression determines global proteostasis of iPSCs preventing the aggregation of misfolded proteins ensued from normal metabolism,” authors of the study write. As such, the team concluded UBR5 to be a modulator of super-vigilant proteostasis of iPSCs.

"The results from our study show that the E3 ubiquitin ligase UBR5 participates in the aggregation of huntingtin in Huntington's disease," Isabel Sáez-Martínez, study author, CECAD, told Rare Disease Report ®. “We show that UBR5 promotes huntingtin degradation through the proteasome, which, in turn, also prevents the accumulation of aggregates in human-iPSCs. These findings uncover a new player involved in Huntington's disease, which expands our knowledge about the disease, thus helping to find new therapeutical targets.”

Dr. Sáez-Martínez added that the team will not follow up on this project in their research lab since the student leading the project is about to graduate. However, they have uploaded their data into a public Consortium (ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD009803) so that the scientific community can expand on it.

"Some of the questions which remain unanswered are whether the interaction between UBR5 and huntingtin is a direct interaction and, if so, which lysine would be the one ubiquitinated by UBR5," she said. "Additionally, although we couldn't find any effect of UBR5 on other poly-glutamine diseases, such as Joseph-Machado disease, UBR5 could be acting on other aggregated-related diseases, and thus, could be important not only for Huntington's disease but for a broad range of other neurodegenerative diseases."

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