Tumor Suppressor Protein May Play Key Role In Amyotropic Lateral Sclerosis

A tumor suppressor protein called von Hippel Lindau may play a key role in the progression of amyotrophic lateral sclerosis.

AsianScientist (Feb. 3, 2016) – Kyoto University researchers have identified several proteins that are key players in the progression of amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease.

One of the main factors triggering the onset of ALS is the malfunctioning of nerve support cells called oligodendrocytes. Recent studies have implied that the malformation and accumulation of a protein called TDP-43 in oligodendrocytes is likely linked to the development of ALS, as with other neurological diseases like Parkinson’s disease.

The current research, published in Scientific Reports, takes this a step further, explaining how TDP-43 accelerates ALS’ characteristic decline in muscle strength.

The research team found that the von Hippel Lindau (VHL) protein, which is associated with a gene that suppresses cancer, strongly binds to malformed versions of the TDP-43 protein in oligodendrocytes.

“TDP-43 appears to be a very fragile protein, and becomes fragmented in the cytoplasm. When this happens, it binds to VHL, which is typically only found in blood vessels, but surprisingly enough, we also found them in oligodendrocytes,” explained lead author Tsukasa Uchida.

VHL forms a complex with cullin 2 (CUL2), a protein that ‘rescues’ the cell in oxygen-deprived conditions, which then proceeds to break down the malformed TDP-43, even under normal conditions.

“CUL2 was known to break down other proteins, but again, our study reports for the first time that it’s also involved in the breakdown of TDP-43,” said Uchida.

Additionally, the team found that when VHL becomes overly abundant, the VHL/TDP-43 complex accumulates in the cytoplasm, forming a protein cluster that is thought to harm the function of oligodendrocytes. Hence, their results suggest that an imbalance in VHL and CUL2 may underlie oligodendrocyte dysfunction in ALS.

“Once we have a clearer idea of how the VHL and CUL2 balance is maintained, I believe we’ll be able to make a huge contribution to the treatment of ALS,” said Makoto Urushitani, the corresponding author of the study.

The article can be found at: Uchida et al. (2016) CUL2-mediated Clearance of Misfolded TDP-43 is Paradoxically Affected by VHL in Oligodendrocytes in ALS.
———

Source: Kyoto University; Photo: Shutterstock.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

Asian Scientist Magazine is an award-winning science and technology magazine that highlights R&D news stories from Asia to a global audience. The magazine is published by Singapore-headquartered Wildtype Media Group.

Related Stories from Asian Scientist