While multiple factors contribute to MS development, doctors consider necroptosis — programmed cell death — to be a driving force. TNFα, a pro-inflammatory cytokine molecule involved in cell signaling, activates necroptosis.
MS affects the central nervous system (CNS), including the brain and spinal cord.
In MS, there is a loss of nerve cells known as oligodendrocytes and damage to myelin, the protective covering of nerve fibers. This disrupts the communication between nerves and results in fatigue, weakness, and difficulty with coordination and balance.
Typically, the body produces TNFα to help fight infection, but in some cases, it can become overactive and start the process of necroptosis. In MS, necroptosis can cause damage to the myelin sheath surrounding nerve cells. Experts think it is one of the primary causes of disability in people with MS.
This article looks at the activation of necroptosis in multiple sclerosis and how it may affect a person.
Necroptosis is a natural process in cells undergoing a specific type of programmed cell death. It differs from other forms of cell death, such as apoptosis, which is a controlled and orderly process. In necroptosis, cells die in a more chaotic and inflammatory manner.
Certain situations expose cells to specific signals or stimuli and activate necroptosis. In MS, the molecule TNFα can activate necroptosis. TNFα is a pro-inflammatory cytokine, which means it plays a role in promoting inflammation in the body.
Proteins in the cells that are involved in necroptosis receive a signal from TNFα and start a chain reaction involving other molecules in the cell. Ultimately, it leads to the formation of a necrosome, a protein complex, that results in cell death.
When necroptosis begins, it triggers a series of events inside cells, ultimately
The events are as follows:
- Signal activation: Certain signals trigger necroptosis, such as inflammation or damage to the cell. In MS, one of the signals is the inflammatory molecule TNFα.
- Protein interaction: Inside the cell, the proteins RIPK1 and RIPK3 interact with each other and form a complex.
- Complex activation: The RIPK1-RIPK3 complex then triggers a series of chemical reactions inside the cell. This complex activates another protein — MLKL.
- Cell membrane rupture: The activated MLKL moves to the cell membrane and causes it to rupture. This rupture leads to the release of cellular contents, resulting in the cell’s death.
- Inflammation response: The release of cellular contents also triggers an inflammatory response in the surrounding tissues. This response can further contribute to the progression of damage and inflammation seen in conditions such as MS.
Necroptosis is typically a tightly regulated process, and under normal circumstances, the body has mechanisms to prevent excessive or inappropriate cell death.
However, in conditions such as MS, there can be disruption to the regulation of necroptosis, leading to the loss of specific cells and contributing to disease progression.
Here is how necroptosis can affect someone with MS:
Oligodendrocyte loss
Necroptosis leads to death of oligodendrocytes, the cells responsible for producing the protective myelin coating around nerve fibers.
In MS, the loss of oligodendrocytes and the subsequent damage to myelin are key features of the disease. This can result in disrupted nerve signals and contribute to symptoms such as problems with the following:
- movement
- coordination
- sensory function
Inflammatory response
Necroptosis triggers an inflammatory response in the surrounding tissues. In MS, this inflammation can exacerbate the immune system’s attack on myelin and lead to further damage. The inflammatory response can also attract immune cells to the affected area, perpetuating the cycle of tissue damage and inflammation.
Disease progression
The activation of necroptosis in MS contributes to the ongoing degeneration of nerve fibers and the loss of oligodendrocytes. This progressive damage can lead to:
- new brain and spinal cord lesions
- worsening neurological symptoms
- increasing disability over time
Doctors do not fully understand the exact reasons why necroptosis occurs in MS. However, researchers believe that
- Inflammatory environment: Chronic inflammation in the CNS is a characteristic of MS. This inflammatory environment — triggered by the immune system — can activate pathways leading to necroptosis. Inflammatory molecules, such as TNFα, play a role in initiating necroptotic cell death.
- Dysregulation of caspase-8: Caspase-8 controls cell death pathways, including necroptosis. In people with MS, there may be defects in the activation of caspase-8, leading to its impaired function. This can result in the activation of alternative cell death pathways, such as necroptosis.
- RIPK1 and RIPK3 interaction: In MS, the interaction between these RIPK1 and RIPK3 proteins becomes dysregulated, leading to the activation of necroptosis.
- Genetic factors: Variations in genes that relate to cell death pathways and immune system function may increase the risk of developing MS and influence the occurrence of necroptosis.
Necroptosis is a form of cell death that occurs in the CNS of individuals with MS. Factors such as TNFα activate it, and it involves the dysregulation of proteins, including RIPK1 and RIPK3.
The activation of necroptosis contributes to the loss of oligodendrocytes and demyelination, which are hallmark features of MS.
Further research into the mechanisms behind necroptosis and developing strategies to modulate or inhibit this process is critical. It provides hope for finding new treatments that can potentially slow down the progression of the disease, protect nerve cells, and improve the quality of life for those living with MS.