Loss of a gene linked to Parkinson’s disease (PD) exposes motor neurons in the brain to increased stress and leads to neurodegeneration, according to a study supported by The ALS Association. The study is published in the journal Cerebral Cortex.
Mutations in the gene, called UCHL1, were first identified as a rare cause of PD and more recently in a non-PD syndrome characterized by loss of upper motor neurons. Upper motor neurons, which link the brain and spinal cord, are also lost in ALS. To better understand the normal role of the gene, researchers developed mice lacking any UCHL1 function. They found that the absence of UCHL1 protein caused selective vulnerability of upper motor neurons. Degeneration of these neurons was accompanied by signs of stress in part of the cell’s protein quality control system, called the endoplasmic reticulum (ER), suggesting that this may contribute to development of the disease.
“These findings emphasize the importance of the ER in motor neuron health,” said Lucie Bruijn, Ph.D., M.B.A., Chief Scientist for The ALS Association. “While UCHL1 itself is not known to be a direct cause of ALS, exploring how it causes degeneration of the brain’s motor neurons is likely to shed light on the same process in ALS.”
The new mouse model will help unravel the molecular mechanisms of brain motor neuron vulnerability and may be useful for testing compounds to improve brain motor neuron health.
The research was performed by 2010 Milton Safenowitz fellow Javier Jara, Ph.D., and Baris Genc, Ph.D., under the direction of Hande Ozdinler, Ph.D., both of Northwestern University in Chicago, Ill.