New gene may affect the upper motor neuron cells in the nervous system, study reveals

A recent genetic finding supports the theory that abnormal lipid (fat) transport pathways inside brain cells cause motor neuron degenerative disorders.

Image Credit: Billion Photos/

Image Credit: Billion Photos/

This idea will open the way for new diagnostic and therapy techniques for this category of diseases. The finding will give answers to those families who have been without a diagnosis in the past.

MNDs (motor neuron degenerative diseases) are a group of neurological conditions. There are currently no therapies available to prevent the disease from developing or progressing. MNDs are caused by mutations in one of a number of genes. Despite the large number of genes linked to MNDs, many individuals are still waiting for a genetic diagnosis.

Professor Andrew Crosby and Dr Emma Baple of the University of Exeter have a long history of study in motor neuron degenerative diseases. Following the finding of 15 genes linked to MNDs, the researchers devised a theory to explain a common cause of MNDs.

The genes they discovered are all involved in the metabolism of lipids in brain cells, particularly cholesterol. The team details the exact lipid pathways that they believe are crucial in the development of MNDs in a new hypothesis published in the renowned neurology journal Brain.

The team has now discovered a novel gene, termed “TMEM63C,” that causes a degenerative disease that damages the nervous system’s higher motor neuron cells. Their recent discovery, which was also reported in Brain, is significant since the protein encoded by TMEM63C is found in the cell area where the lipid processing pathways researchers discovered work. This supports the theory that MNDs are induced by abnormal lipid processing, particularly cholesterol.

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 neuron degenerative diseases. It also enables new diagnoses and answers to be readily provided for families affected by some forms of MND.”

Andrew Crosby, Professor, Human Genetics, University of Exeter

MNDs cause problems in the nerve cells that drive voluntary muscular movements including walking, speaking, and swallowing. MNDs come in a variety of types, each with its own set of clinical symptoms and severity. The motor neuron cells get injured and may die as the disease develops. As a result, the muscles that rely on those nerve transmissions weaken and worsen over time.

If the idea is proven, scientists may be able to utilize patient samples to anticipate the duration and severity of a disease in a person, as well as track the effects of possible new treatments created to treat these conditions.

The team utilized cutting-edge genetic sequencing techniques to examine the genomes of three families with members suffering from hereditary spastic paraplegia, a group of MNDs in which motor neurons in the upper section of the spinal cord miscommunicate with muscle fibers, resulting in muscle stiffness, weakness, and wasting. These findings revealed that the condition was caused by mutations in the TMEM63C gene.

The researchers also conducted tests to understand more about the functional importance of the TMEM63C protein inside the cell in partnership with Dr Julien Prudent’s group at the Medical Research Council Mitochondrial Biology Unit at the University of Cambridge.

The Cambridge team discovered that a subset of TMEM63C is localized at the interface between the two critical cellular organelles, the endoplasmic reticulum and the mitochondria, a region of the cell needed for lipid metabolism homeostasis and suggested by the Exeter team to be important for the development of MNDs, using cutting-edge microscopy methods.

Dr Luis-Carlos Tabara Rodriguez, a Postdoctoral Fellow in Dr Prudent’s group, discovered that TMEM63C regulates the shape of both the endoplasmic reticulum and mitochondria, which might represent its role in the regulation of these organelles’ activities, such as lipid metabolism homeostasis.

From a mitochondrial cell biologist point of view, identification of TMEM63C as a new motor neuron 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.”

Dr Julien Prudent, Mitochondrial Biology Unit, Medical Research Council, University of Cambridge

Dr Emma Baple, of the University of Exeter, added, “Understanding precisely how lipid processing is altered in motor neuron 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. Finding this gene is another important step towards these important goals.”

This research was partially financed by the Halpin Trust, a foundation that supports studies that have a significant and long-term impact on healthcare, wildlife conservation, and the environment.

Claire Halpin, who co-founded the charity with her husband Les, states, “The Halpin Trust are extremely proud of the work ongoing in Exeter, and the important findings of this highly collaborative international study. We’re delighted that the Trust has contributed to this work, which forms part of Les’s legacy. He would also have been pleased, I know.”

The HSP Support Group is a UK charity that assists persons with Hereditary Spastic Paraplegia (HSP).

Adam Lawrence, the Group’s Chair noted, “Finding a new type of HSP is extremely important as it helps reduce the uncertainty which people with the condition often have on their diagnosis journey. The work of the team in Exeter investigating HSP and its genetic causes over many years is world-leading and has increased the global understanding of HSP. Their work is important providing much needed answers for people with HSP, and developing treatments.”

Journal reference:

Tábara, L. C., et al. (2022) TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia. Brain.


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