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What happens in ALS?
Although research is making great strides on the knowledge of the mechanisms underlying the disease, there is not any effective treatments. For this reason, researchers are investigating the pathological mechanisms that lead to degeneration of motor neurones focusing on several fronts.
Below are some of the mechanisms that are suspected to be involved in motor neurone degeneration.
Aggregation. Abnormal clumps (aggregates) of protein molecules cluster inside motor neurones affected by ALS, disrupting their normal functioning.
Altered RNA metabolism. Production and transport of RNA molecules, needed to build proteins, may be altered and the production of proteins could be adversely affected and cause the disease.
Abnormalities of Structural Proteins. Because of the unusual length of their axons, motor neurons require large quantities of a protein known as neurofilaments, one of the building blocks of structural fibers that help the axon maintain its shape. In patients with ALS, as well as other neurodegenerative diseases, neurofilament proteins fail to assemble properly, creating disorganized fibers or abnormal accumulations (aggregations) of neurofilament within the motor neuron. These abnormalities affects also the cytoskeleton, the cellular ‘scaffolding’ that ensures that the shape and structure of motor neurones and other cells is maintained, causing cell degeneration.
Altered communication networks. The nervous system is constantly transmitting electrical signals to muscles via motor neurons. The electrical impulse travels along the motor neuron’s axon; when it reaches the axon’s end, the neuron “fires”—the electrical message is converted into a chemical message (a neurotransmitter) that quickly diffuses across the synapse to a second motor neuron (or the target muscle). For many motor neurones this chemical messenger is glutamate, which in high concentrations can be toxic and cause excitotoxicity. The need to constantly control the movement of muscles, limbs, and respiration creates a heavy demand on motor neurons, making them, in theory, prone to excitotoxicity. Riluzole, the first FDA-approved ALS drug, is believed to act on the glutamate system.
Disruption of Axonal Transport. In most cells, critical substances are produced in the cell nucleus and surrounding structures and are then transported to regions of the cell where they are needed. Motor neurones are large cells, with the largest axons measuring up to one metre in length. It is necessary that their transport systems for moving nutrients, waste and components from one end of the neurone to the other work well. This unusual requirement for transport may be another feature of the motor neuron that makes it vulnerable to disease. Recent research in both mouse models and humans suggest that disruption of axonal transport may play a role in ALS. If any part of the transport system becomes faulty, it may cause disruption to the whole system and lead to degeneration of the motor neurone.
Oxidative damage. Oxygen free radicals are toxic chemicals formed as a normal by-product of cellular processes, which are normally scavenge by antioxidants. In ALS however, the motor neurones’ own antioxidant defence pathways may be suppressed, leading to a toxic build-up of waste. The recent approve drug for ALS, edaravone, seems to act on this pathway. However, studies of antioxidant supplements in mouse models showed that they do not significantly alter the course of the disease.
Mitochondrial Damage. With their elevated energy demand and metabolic rate, motor neurons have a large number of mitochondria—organelles that form the “power plants” of all cells. Abnormalities in mitochondria have been found in several neurodegenerative diseases, including ALS. Studies in the SOD1 mouse model have helped researchers study these changes in detail, bringing this area of research to the fore in recent years.
Lack of nerve nourishing factors. One of the surprising discoveries in recent years is that growth factor previously thought to be unrelated to motor neuron disease are potentially involved in ALS development. There is some evidence that motor neurones become more susceptible to ALS because of the lack of nutrients. One form of motor neurone nutrients that are likely to be in shortage in ALS, is a group of chemicals called neurotrophic factors, literally meaning ‘nerve nourishing factors’.
Problematic neighbours. Motor neurones are surrounded by cells called glia, which normally provide the neurones with support and nourishment. However, researchers have now come to realise that glial cells, such as oligodendrocytes, can in fact contribute to motor neurone degeneration if they lose their supportive properties and become toxic.
Inflammation. Inflammation is part of the immune system’s protective reaction to tissue damage or invasion by microbes. It is a process that should help heal. But sometimes the inflammation that accompanies illness or injury is counterproductive. Inflammation can turn into an unnecessary attack on the body’s own tissues, as in arthritis or autoimmune disease. There is increasing evidence that inflammation accompanies the death of motor neurons in ALS. The glia cells, called microglia, that usually protect the Central Nervous System from external attacks, supporting their neighboring neurons can become over active acting and produce unwanted effects and perhaps add to the damage.
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