Motor neurone degenerative diseases are caused by abnormal lipid processing pathways inside brain cells


A new genetic discovery adds weight to a theory that motor neurone degenerative diseases are caused by abnormal lipid (fat) processing pathways inside brain cells.

This theory will help pave the way to new diagnostic approaches and treatments for this group of conditions. The discovery will provide answers for certain families who have previously had no diagnosis.

Motor neurone degenerative diseases (MNDs) are a large family of neurological disorders. Currently, there are no treatments available to prevent onset or progression of the condition. MNDs are caused by changes in one of numerous different genes. Despite the number of genes known to cause MNDs, many patients still remain without a much-needed genetic diagnosis.

A University of Exeter team led by Professor Andrew Crosby and Dr. Emma Baple has a long history of research in motor neurone degenerative diseases. The team developed a hypothesis to explain a common cause of MNDs stemming from their discovery of 15 genes responsible for MNDs.

The genes they identified are all involved in processing lipids – in particular cholesterol—inside brain cells. in the new hypothesis published in the leading neurology journal Brain, describes the specific lipid pathways that the team believe are important in the development of MNDs.

Now, the team has identified a further new gene – named “TMEM63C” – which causes a degenerative disease that affects the upper motor neurone cells in the nervous system. Also published in Brain, their latest discovery is important as the protein encoded by TMEM63C is located in the region of the cell where the lipid processing pathways they identified operate. This further bolsters the hypothesis that MNDs are caused by abnormal processing of lipids including cholesterol.

Professor Andrew Crosby, at the University of Exeter, said: “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 affected by some forms of MND”

MNDs affect the nerve cells that control voluntary muscle activity such as walking, speaking and swallowing. There are many different forms of MNDs which have different clinical features and severity. As the condition progresses, the motor neurone cells become damaged and may eventually die. This leads to the muscles, which rely on those nerve messages, gradually weakening and wasting away.

If confirmed, the theory could lead to scientists to use patient samples to predict the course and severity of the condition in an individual, and to monitor the effect of potential new drugs developed to treat these disorders.

In the latest research, the team used cutting-edge genetic sequencing techniques to investigate the genome of three families with individuals affected by hereditary spastic paraplegia – a large group of MNDs in which the motor neurons in the upper part of the spinal cord miscommunicate with muscle fibres, leading to symptoms including muscle stiffness, weakness and wasting.

These investigations showed that changes in the TMEM63C gene were the cause of the disease. In collaboration with the group led by Dr. Julien Prudent at the Medical Research Council Mitochondrial Biology Unit at the University of Cambridge, the team also undertook studies to learn more about the functional relevance of the TMEM63C protein inside the cell.

Using state-of-the-art microscopy methods, the Cambridge team’s work showed that a subset of TMEM63C is localised at the interface between two critical cellular organelles, the endoplasmic reticulum and the mitochondria, a region of the cell required for lipid metabolism homeostasis and proposed by the Exeter team to be important for the development of MNDs.

In addition to this specific localisation, Dr. Luis-Carlos Tabara Rodriguez, a Postdoctoral Fellow in Dr. Prudent’s lab, also uncovered that TMEM63C controls the morphology of both the endoplasmic reticulum and mitochondria, which may reflect its role in the regulation of the functions of these organelles, including lipid metabolism homeostasis.

Dr. Julien Prudent, of the MRC Mitochondrial Biology unit, said: “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.”

Dr. Emma Baple, of the University of Exeter, said: “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. Finding this gene is another important step towards these important goals”

The Halpin Trust, a charity who support projects which deliver a powerful and lasting impact in healthcare, nature conservation and the environment, part-funded this research. Claire Halpin, the charities’ co-founder with her husband Les said “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 providing help for people diagnosed with Hereditary Spastic Paraplegia (HSP). Adam Lawrence, the Group’s Chair said “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.”

The new study is entitled “TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia,” and is published in Brain.

Hereditary spastic paraplegia (HSP) was first described by Strumpell and Lorrain in the late 19th century and was initially considered to be a small group of Mendelian disorders. However, subsequent advancements in our understanding of the genetic architecture of HSP have led to it being recognized as one of the most genetically (>80 causative genes) and clinically heterogeneous of inherited diseases. HSP is characterized clinically by lower-limb spasticity and weakness, and pathologically by the retrograde degeneration of motor neurons.1,2 HSP may be subdivided into pure and complex forms, depending on whether other system involvement or neurological features accompany the cardinal clinical sign of progressive lower-limb spastic weakness.

Autosomal recessive forms account for an estimated 25–30% of HSP patients, typically involving complex forms of HSP with additional clinical features including impaired vision and hearing, cognitive impairment, seizures and peripheral neuropathy.1 At present, there is no cure for the condition and treatments are largely symptomatic, involving the use of antispasmodic agents such as baclofen, progabide and dalfampridine.3 Increasing understanding of the biological basis of HSP is supporting the development of new treatments, which have the potential to be personalized depending on the underlying genetic cause.3

The significant molecular heterogeneity of HSP is indicative of a complex pathomolecular aetiology, which remains poorly understood with genes associated with the condition being implicated in a wide array of cellular processes. These include protection against oxidative stress, DNA repair, metabolism of neuroprotective steroids, myelin sheath stabilization, axonal growth and subcellular transport,4 all proposed to lead to axonal failure and progressive lower-limb spasticity characteristic of the condition.1,3

Recently, increasing genetic and molecular evidence suggests a potential central role for aberrant lipid metabolic processes in particular involving endoplasmic reticulum (ER), mitochondria and other organelles.2 Many of the genes associated with motor neuron degenerative diseases, including HSP, have been linked in molecular studies with lipid metabolic pathways, in particular involving molecular flux between the ER and mitochondria.

ER and mitochondrial compartments connect via mitochondria-ER contact sites (MERCs),2 which are distinct structural domains characterized by the close apposition of both ER and mitochondrial membranes, and establish a molecular platform crucial for signalling and metabolite flux between both organelles in order to maintain organelle and cellular homeostasis.5–7 The ER is the main site of phospholipid biosynthesis and provides lipid precursors to other membranes, including mitochondria.8,9

Phospholipid transport from the ER to mitochondria via MERCs enables the synthesis of essential mitochondrial phospholipids including cardiolipin, phosphatidylserine and phosphatidylethanolamine.10 These molecular pathways provide the essential building blocks of biological membranes, and alterations in genes encoding the proteins regulating these pathways have been linked with HSP.2,10–12

Thus, maintaining MERCs integrity is increasingly recognized as being critical for phospholipid metabolism and also cellular homeostasis more widely,13 and gene alterations leading to impaired MERCs function probably form a molecular theme common to many neurological disorders.2,14

The osmosensitive calcium (OSCA)/transmembrane protein 63 (TMEM63) protein family members entail a newly identified family of mechanical ion channels activated by membrane tension, which are conserved across eukaryotes.15 The family comprises three members: TMEM63A, TMEM63B and TMEM63C, the function of which has not been extensively explored in mammals. Zhao et al.16 identified a possible role of TMEM63 proteins as osmoreceptor transduction channels, and found that expression of all three members was required in cell transfection studies for channel activity.

Studies on TMEM63C plant orthologues (AtCSC1 and OSCA1) indicate that it may indeed function as a Ca2+ permeable cation channel that is activated by hyperosmotic stress.15,16 While previous studies of TMEM63C are restricted to its plant orthologues, maintenance of the ionic and osmotic composition and volume of fluids is crucial for the normal functioning of the brain,17 of clear relevance should the mammalian (and human) TMEM63C orthologues possess similar functionalities.

Interestingly, studying the structure of ER-localized OSCA1.2, a plant orthologue of TMEM63C, revealed striking topological similarities with the transmembrane protein TMEM16.18,19 Dysfunction of different TMEM16 proteins (also known as anoctamins) is associated with several neurologic disorders, including muscle disease, cerebellar ataxia and dystonia.20 Importantly, one member of this family, TMEM16K, has been proposed to regulate endosomal function at ER-endosome contact sites.

Furthermore, the yeast TMEM16 orthologue, Ist2p, is a tether protein connecting the ER and the plasma membrane, identifying a role of some TMEM16 family members at membrane contact sites.21,22 Here we present genetic, clinical and molecular data that identify biallelic variants in TMEM63C probably leading to loss of function, as a cause of both pure and complex HSP. Our molecular studies determine that TMEM63C is an ER-localized protein enriched at MERCs, and that TMEM63C knockdown is associated with mitochondrial and ER morphological defects, revealing a previously unidentified role of TMEM63C in mediating organelle homeostasis.

reference link:

More information: Luis Carlos Tábara et al, TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia, Brain (2022). DOI: 10.1093/brain/awac123


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