Look at all those interesting cytokines that leron

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In fact, motor neuron degeneration appears to be dependent on neighbouring glia expressing mutant proteins. For example, studies have shown that high expression of mutant SOD1 in either most or all motor neurons of mice is insufficient for disease onset, whereas mutant SOD1 expressed within microglia is required for disease to occur. Additionally, extracellular mutant SOD1 from the SOD1G93A mouse model of ALS does not cause detectable direct killing of motoneurons in culture, but it activates microglia which then release toxic factors that lead to motor neuron death . In line with this, reducing the expression of mutant SOD1 within microglia slows disease progression. Similarly, deletion of mutant SOD1 within astrocytes, oligodendrocytes and NG2 glial cells delays disease progression and improves survival. Therefore, although ALS was once considered a motor neuron disease, it is now known as a multi-cellular and multi-systemic disease, with motor neuron death being primarily driven by glial cell pathology as well as a convergence of other damaging mechanisms such as inflammatory conditions.

The levels of several pro-inflammatory cytokines are altered in ALS, suggesting the presence of inflammation. For example, an increase in the protein expression levels of tumour necrosis factor (TNF), interleukin (IL)-8, IL-12, IL-17(A), interferon (IFN)-γ and monocyte chemoattractant protein (MCP)-1 in the blood serum and/or cerebrospinal fluid (CSF) of ALS patients has been observed by at least two independent studies. Moreover, increased expression of several chemokines was found in the CSF of ALS patients. Although the expression of IL-1β, IL-2, IL-6 and IL-15 has been found upregulated in the serum or CSF of ALS patients in some studies, it remained unchanged in other studies, likely due to the different detection methods employed. Furthermore, increased production of TNF and IL-1β, as well as reactive oxygen species (ROS) and prostanoids, was observed in spinal cord tissue from ALS patients . It has also been shown that chronic administration of IL-1β results in neurodegeneration, whereas IL-1β depletion or IL-1 receptor antagonism attenuates inflammation and prolongs the lifespan of ALS mouse models, providing further evidence of the importance of inflammation in the pathology of ALS.

It was also shown that the level of microglial activation parallels motor neuron degeneration in ALS patients, and that microglia expressing mutant SOD1G93A in mice are more activated than wild-type microglia [98]. Furthermore, mice overexpressing SOD1 show an increase in M1-like microglia, and SOD1G93A mutations in rat microglia result in accelerated disease progression, compared to wild-type microglia.

The transcription factor NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is induced by certain pro-inflammatory cytokines and regulates genes responsible for the innate and adaptive immune response. Several studies have shown that this transcription factor is upregulated in glial cells of both sALS and fALS patients. Interestingly, the ALS-associated gene optineurin negatively regulates pro-inflammatory-mediated NF-κB activation [104], and loss-of-function mutations in this gene are seen in some ALS patients. Consistent with this, SOD1G93A mice exhibit NF-κB hyperactivation in microglia, while NF-κB inhibition extends the survival of these mice by slowing disease progression.

Studies suggest that exposure to low levels of systemic signalling molecules associated with ageing and chronic inflammation (i.e. microglial “priming”) can exacerbate the microglial response to a second local stimulus, such as the presence of protein aggregates characteristic of neurodegenerative diseases, potentiating tissue damage. Additionally, it was recently shown that IL-1β-mediated activation of astrocytes overexpressing wild-type FUS alter their cross-talk with microglia so that microglia acquire a pro-inflammatory profile resembling the phenotype seen in ALS. It was further suggested that the mechanism of this activation involved an increase in the level of prostanoids released by these astrocytes; however, no evidence was found to support this. Instead, other pro-inflammatory cytokines such as IL-5, IL-6, IL-7, IL-15 and other molecules under astrocytic NF-κB transcriptional control have been suggested as likely candidates driving microglial activation.

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