Multiple sclerosis (MS), a common neurodegenerative disease of the CNS, is characterized by the loss of oligodendrocytes and demyelination. Tumor necrosis factor α (TNF-α), a proinflammatory cytokine implicated in MS, can activate necroptosis, a necrotic cell death pathway regulated by RIPK1 and RIPK3 under caspase-8-deficient conditions. Here, we demonstrate defective caspase-8 activation, as well as activation of RIPK1, RIPK3, and MLKL, the hallmark mediators of necroptosis, in the cortical lesions of human MS pathological samples. Furthermore, we show that MS pathological samples are characterized by an increased insoluble proteome in common with other neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). Finally, we show that necroptosis mediates oligodendrocyte degeneration induced by TNF-α and that inhibition of RIPK1 protects against oligodendrocyte cell death in two animal models of MS and in culture. Our findings demonstrate that necroptosis is involved in MS and suggest that targeting RIPK1 may represent a therapeutic strategy for MS
Necrosis is a form of cell injury that results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma that result in the unregulated digestion of cell components. In contrast, apoptosis is a naturally occurring programmed and targeted cause of cellular death. Cells that die due to necrosis do not follow the apoptotic signal transduction pathway but rather various receptors are activated that result in the loss of cell membrane integrity and an uncontrolled release of products of cell death into the extracellular space. This initiates in the surrounding tissue an inflammatory response which prevents nearby phagocytes from locating and eliminating the dead cells by phagocytosis.
Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis (programmed cell death), necrosis, and inflammation
Caspases are essential in cells have been termed “executioner” proteins for their roles in the cell. Failure of apoptosis is one of the main contributions to tumour development and autoimmune diseases;
Initiator caspases (e.g., CASP2, CASP8, CASP9, and CASP10) cleave inactive forms of effector caspases, thereby activating them. Effector caspases (e.g., CASP3, CASP6, CASP7) in turn cleave other protein targets to trigger the cell death. The initiation of this cascade reaction is regulated by caspase inhibitors.
Caspase8 is invovled in the control of white cell numbers but it also turns up in in inclusion bodies in neurodegenerative diseases. Inclusion bodies are nuclear or cytoplasmic aggregates of stainable substances, usually proteins. One of the best known inclusion body is the Lewy Body in diseases such as Parkinsons disease. A Lewy body is composed of the protein alpha-synuclein associated with other proteins, such as ubiquitin, neurofilament protein, and alpha B crystallin. Tau proteins may also be present, and Lewy bodies may occasionally be surrounded by neurofibrillary tangles, which occur in Alzheimers Disease. Some of the proteins which don’t dissolve in water (insoluble) or the cytoplasm of a cell found in MS are also found in other neurodegenerative diseases. Are these a cause of nerve loss? or are these a consequence of cell stress and their attempt to stop nerve damage?. Probably a bit of both.
In this study they show that nerves in the cortex are probably dying, which is going to contribute to progressive MS. They show that
Receptor-interacting serine/threonine-protein kinase 1 RIPK1) is activated in MS lesions. RIPK1 is known to have function in a variety of cellular pathways including the NF-κB pathway which will promote cytokine release and programmed necrotic cell death (necroptosis). RIPK3 is a component of the tumor necrosis factor (TNF) receptor-I signaling complex. It was found that RIPK1 stimulates Tumour necrosis factor mediated damage of the myelin forming oligodendrocytes. So if they knockout RIPK3 there was less oligodedrocyte damage and then block of RIPK1 with an inhibitor also limited oligodendrocyte damage.
It has been reported that brain cholesterol can stimulate RIPK1 I and cause nerve damage, I wonder, Is this how statins have a neuroprotective effects in secondary progressive MS?. It makes more sense that via an immunological effect. Is this why cholesterol pathways have been implicated in pathology of Alzheimers disease