It is well understood that the neurodegenerative disorder Huntington’s disease is caused by an N-terminal polyQ-expansion (>35) in the Huntingtin (HTT) gene. This mutation leads to axonal degeneration and significant neuronal death.
Now, new work builds off of previous findings that two specific signaling proteins, GSK3ß and ERK1, were expressed more in the neurons of Huntington’s disease patients. Researchers prevented the two proteins from functioning in the neurons of fruit fly larvae that have a mutant HTT. This inhibition of GSK-3ß led to fewer defects in the axonal transport process and less neuronal cell death, while inhibiting ERK1 led to more transport problems and cell death.
This work is published in Nature Cell Death & Disease in the paper, “Opposing roles for GSK3β and ERK1-dependent phosphorylation of huntingtin during neuronal dysfunction and cell death in Huntington’s disease.”
The team used “quantitative mass spectrometry-based proteomics on HTT-containing light vesicle membranes isolated from healthy and HD iPSC-derived neurons” and found “significant changes in the proteome and kinome of signal transduction, neuronal translation, trafficking, and axon guidance-related processes.”
A comparison of healthy human neurons with neurons of a Huntington’s disease patient, where GSK3ß and ERK1 were upregulated. [Krzystek and Gunawardena/University at Buffalo]
“With these findings, we propose that ERK1 may protect neurons in the face of Huntington’s disease, while GSK3ß may exacerbate Huntington’s disease,” said Shermali Gunawardena, PhD, associate professor of biological sciences in the University at Buffalo’s College of Arts and Sciences. “Therapeutics may one day be able to target these signaling proteins in different ways—inhibiting GSK3ß and boosting ERK1—to treat this severe and fatal neurological disorder.”
The kinases GSK3ß and ERK1 were upregulated in neurons with Huntington’s disease when compared with normal neurons. Inhibiting GSK3ß in fruit fly larvae with Huntington’s disease decreased their axonal blockages and neuronal cell death. The fruit flies were able to crawl better.
“So, while GSK3ß typically plays a positive role in neuronal function, it seems it may actually make a bad situation worse when faced with a mutant HTT,” Gunawardena said.
Conversely, inhibiting ERK1 increased axonal blockages and cell death.
“The level of ERK1 is clearly important for Huntington’s disease, but whether it’s actually modulating the mutant HTT is unclear,” said Thomas Krzystek, who received a PhD in biological sciences from UB in 2022 and is now a senior scientist at AbbVie. “Either way, the signaling from this ERK1 pathway is neuroprotective in the context of Huntington’s disease.”
The team also tried elevating the levels of ERK1 and found it decreased traffic blockages and cell death.
“So long as it doesn’t affect other processes that ERK1 might be involved in, future treatment could potentially increase a patient’s levels of ERK1 to mitigate their neuronal cell death,” Gunawardena said. “There’s not much that can be done once cells have died, so our whole research is trying to figure out these key, early processes that lead to cell death and whether that can be prevented.”
Taken together, the results propose “two novel pathways in which GSK3β phosphorylation events exacerbate and ERK phosphorylation events mitigate HD-dependent neuronal dysfunction, highlighting a highly druggable pathway for targeted therapeutics using already available small molecules.”
The post Opposing Forces: How GSK3β and ERK1 Phosphorylation Shape Huntington’s Disease appeared first on GEN - Genetic Engineering and Biotechnology News.
Now, new work builds off of previous findings that two specific signaling proteins, GSK3ß and ERK1, were expressed more in the neurons of Huntington’s disease patients. Researchers prevented the two proteins from functioning in the neurons of fruit fly larvae that have a mutant HTT. This inhibition of GSK-3ß led to fewer defects in the axonal transport process and less neuronal cell death, while inhibiting ERK1 led to more transport problems and cell death.
This work is published in Nature Cell Death & Disease in the paper, “Opposing roles for GSK3β and ERK1-dependent phosphorylation of huntingtin during neuronal dysfunction and cell death in Huntington’s disease.”
The team used “quantitative mass spectrometry-based proteomics on HTT-containing light vesicle membranes isolated from healthy and HD iPSC-derived neurons” and found “significant changes in the proteome and kinome of signal transduction, neuronal translation, trafficking, and axon guidance-related processes.”
A comparison of healthy human neurons with neurons of a Huntington’s disease patient, where GSK3ß and ERK1 were upregulated. [Krzystek and Gunawardena/University at Buffalo]
“With these findings, we propose that ERK1 may protect neurons in the face of Huntington’s disease, while GSK3ß may exacerbate Huntington’s disease,” said Shermali Gunawardena, PhD, associate professor of biological sciences in the University at Buffalo’s College of Arts and Sciences. “Therapeutics may one day be able to target these signaling proteins in different ways—inhibiting GSK3ß and boosting ERK1—to treat this severe and fatal neurological disorder.”
The kinases GSK3ß and ERK1 were upregulated in neurons with Huntington’s disease when compared with normal neurons. Inhibiting GSK3ß in fruit fly larvae with Huntington’s disease decreased their axonal blockages and neuronal cell death. The fruit flies were able to crawl better.
“So, while GSK3ß typically plays a positive role in neuronal function, it seems it may actually make a bad situation worse when faced with a mutant HTT,” Gunawardena said.
Conversely, inhibiting ERK1 increased axonal blockages and cell death.
“The level of ERK1 is clearly important for Huntington’s disease, but whether it’s actually modulating the mutant HTT is unclear,” said Thomas Krzystek, who received a PhD in biological sciences from UB in 2022 and is now a senior scientist at AbbVie. “Either way, the signaling from this ERK1 pathway is neuroprotective in the context of Huntington’s disease.”
The team also tried elevating the levels of ERK1 and found it decreased traffic blockages and cell death.
“So long as it doesn’t affect other processes that ERK1 might be involved in, future treatment could potentially increase a patient’s levels of ERK1 to mitigate their neuronal cell death,” Gunawardena said. “There’s not much that can be done once cells have died, so our whole research is trying to figure out these key, early processes that lead to cell death and whether that can be prevented.”
Taken together, the results propose “two novel pathways in which GSK3β phosphorylation events exacerbate and ERK phosphorylation events mitigate HD-dependent neuronal dysfunction, highlighting a highly druggable pathway for targeted therapeutics using already available small molecules.”
The post Opposing Forces: How GSK3β and ERK1 Phosphorylation Shape Huntington’s Disease appeared first on GEN - Genetic Engineering and Biotechnology News.