Research led by the University of Exeter and the University of Cambridge in the U.K. adds weight to the theory that motor neurone diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, hereditary spastic paraplegias, and others, are caused by abnormal lipid processing.
In the current study, published in the journal Brain, the scientists showed that genetic variants in the transmembrane protein 63C (TMEM63C) gene are linked to some hereditary spastic paraplegias.
“We’re extremely excited by this new gene finding, as it is consistent with our hypothesis that the correct maintenance of specific lipid processing pathways is crucial for the way brain cells function, and that abnormalities in these pathways are a common linking theme in motor neurone degenerative diseases. It also enables new diagnoses and answers to be readily provided for families,” said Andrew Crosby, a professor at the University of Exeter and co-lead author on the study, in a press statement.
There are many different types of motor neurone diseases, most of which are rare, impacting more than 70,000 people in North America. A previous theory by the researchers involved in the current study and others has implicated abnormal lipid metabolism as a causative factor in these serious and often life-threatening conditions.
Crosby and team identified genetic variants in the TMEM63C gene in individuals from three families with hereditary spastic paraplegias, an upper motor neuron disease with similar presentation to cerebral palsy. Mutations in this gene were found to be causative in the individuals tested.
The protein encoded by the TMEM63C gene was investigated and found to be present in the endoplasmic reticulum, an area of the cell involved in protein synthesis and transport, and the areas connecting this part of the cell to the energy providing mitochondria, an area important for lipid metabolism. Further analysis looking at function showed this protein plays a role in shaping the endoplasmic reticulum and the mitochondria.
“From a mitochondrial cell biologist point of view, identification of TMEM63C as a new motor neurone degenerative disease gene and its importance to different organelle functions reinforce the idea that the capacity of different cellular compartments to communicate together, by exchanging lipids for example, is critical to ensure cellular homeostasis required to prevent disease,” noted Julien Prudent, a researcher at the MRC Mitochondrial Biology unit in Cambridge and co-lead author of the study.
Finding the link between lipid abnormalities and motor neurone diseases is just the first step. The researchers hope the research can help to develop better treatments for this diverse group of neurological disorders.
“Understanding precisely how lipid processing is altered in motor neurone degenerative diseases is essential to be able to develop more effective diagnostic tools and treatments for a large group of diseases that have a huge impact on people’s lives,” said Emma Baple, a researcher at the University of Exeter and co-lead author of the study.
