ALS (Lou's Gehrig's disease) is characterized by skeletal muscle weakness, spasticity and intense muscle wasting. By analogy with what happens following a spinal cord injury, scientists hypothesized a century ago that ALS is an upper motor neuron disease.
Scientists being very conservative, this hypothesis is still in force. ALS is even called MND in the UK because the wide and diverse spectrum of symptoms of ALS makes it difficult to categorize it as a single disease while it shares aspects with other neurodegenerative diseases such as FTD or Alzheimer's disease. Parkinsons.
However, the scientific literature displays a wide range of opinions on this subject since approximately a quarter of the articles argue for a disease that begins in the neuromuscular junctions or even in the muscles.
It is hardly surprising that few alternative hypotheses have developed about ALS because motor neurons are located entirely within the CNS, with a tight barrier separating it from the rest of the body. The CNS has its own mechanisms which are entirely different from the rest of the body, sometimes scientists joke that we are a chimera of two different organisms: the CNS and the rest of the body. However, it seems curious that a disease would only affect the upper motor neurons and not the other neurons, especially since ALS is sometimes associated with disorders that have nothing to do with motor, such as dementia.
Thus, research on skeletal muscle in ALS is always welcome on this blog. Mutations in the fused sarcoma (FUS) gene have been reported to be the most common genetic cause of early-onset amyotrophic lateral sclerosis (ALS).
Yet, the role of FUS in muscle degeneration remains unclear. In this study, Chinese scientists investigated the distribution of FUS proteins in skeletal muscle fibers in ALS-FUS. Their data show that mislocalized cytoplasmic FUS in the unaggregated form represented a remarkable pathologic feature in affected muscle fibers in ALS-FUS.
Additional studies found that cytoplasmic FUS colocalized with some mitochondria and was associated with mitochondrial swelling.
RNA sequencing and quantitative real-time polymerase chain reaction analyses indicated downregulation of the key subunits of mitochondrial oxidative phosphorylation complexes in the affected skeletal muscle in ALS-FUS patients.
Further immunoblot analysis showed increased levels of FUS, but decreased levels of Cox I (subunit of complex IV) in ALS-FUS patients compared with age-matched controls. Cytochrome c oxidase is a key enzyme in aerobic metabolism.
Mutations in Cox I lead to a wide variety of clinical manifestations ranging from isolated myopathy to a severe multisystem disease affecting multiple organs and tissues. Symptoms may include liver dysfunction, hypotonia, muscle weakness, exercise intolerance, delayed motor development, mental retardation, or a CNS disease: Leigh disease.
As this demonstrate association of cytoplasmic mislocalized FUS with mitochondrial dysfunction in skeletal muscle, this is further evidence that ALS is not just an upper motor neuron disease.
