Multiple Sclerosis Severity: Is it Brain Resilience or Immune Aggression?
A recent study has identified a specific gene, N-Acetylglucosamine Kinase (NAGK), that may play a critical role in determining the severity of multiple sclerosis (MS). This finding challenges the existing hypothesis that MS severity is primarily determined by brain tissue resilience. Instead, it suggests that the immunometabolic gene NAGK in immune cells, particularly classical monocytes, could be the key.
The Genetic Link: rs10191329 and NAGK
The story begins with the discovery of a single nucleotide polymorphism (SNP), rs10191329, which has been linked to MS severity in two large, independent studies. An SNP is a variation in a single DNA building block (nucleotide). The location of this variation can impact disease.
Previous research suggested that rs10191329 regulates genes involved in brain resilience and cognitive abilities. However, a new analysis points to NAGK as the primary target of rs10191329. This gene is involved in glucose metabolism and exerts major immune functions through the regulation of the NOD2 pathway.
Challenging the "Brain Resilience" Hypothesis
The initial study proposed that rs10191329 influences MS severity by regulating the expression of ZNF638 and DYSF in neural cells, thus impacting brain tissue resilience. However, the current study argues that this conclusion is based on a gene prioritization strategy that relies heavily on the proximity of rs10191329 to these genes. The authors of the current study suggest this approach may be unreliable because target genes can be located far from their regulatory SNP.
Furthermore, evidence from the Open Targets Genetics (OTG) platform reveals that rs10191329 does not correlate with expression quantitative traits (eQTLs) in neural cells or tissues. Instead, rs10191329 is associated with eQTLs in blood cells and interferon-gamma (IFN-γ)-stimulated monocytes for NAGK. It also affects plasma levels of NAGK.
NAGK: An Immunometabolic Player in MS
NAGK is highly expressed in immune cells, especially dendritic cells, monocytes, and macrophages. Among blood-circulating immune cells, classical monocytes exhibit the highest NAGK mRNA levels. This suggests that rs10191329-mediated regulation of NAGK primarily affects classical monocytes.
In monocytes, NAGK interacts with a network of proteins involved in glycogenesis and neoglucogenesis, which is the generation of glucose from non-carbohydrate carbon substrates. This interaction may influence the metabolic status of monocytes, particularly under MDP-NOD2 activation. Moreover, NAGK plays a role in the recycling of glycosylated proteins, potentially affecting the glycosylation of key MS-related immune molecules.
Potential Pathways Linking NAGK to MS Severity
The study proposes three potential pathways through which NAGK may influence MS severity:
* The NAGK-MDP-NOD2 regulatory pathway: NOD2 is an immunoregulatory receptor, and its activation in myeloid cells can foster immune tolerance. A decrease in NAGK expression may disrupt this pathway, leading to increased MS severity.
* The glycolytic pathway: NAGK interacts with proteins involved in glucose metabolism in monocytes. This interaction may affect the metabolic reprogramming of monocytes during inflammation.
* The glycosylation pathway: NAGK participates in the recycling of glycosylated proteins. Alterations in NAGK expression may affect protein glycosylation in immune cells, influencing MS severity.
Implications for MS Research and Treatment
This research shifts the focus from brain resilience to the role of immune cells and immunometabolism in MS severity. It suggests that targeting the NAGK/NOD2 pathway could be a promising therapeutic strategy.
Specifically, the study highlights the potential of:
* Stimulating NAGK expression
* Systemic administration of NOD2 agonists
While neuroprotective treatments remain important, this study indicates that the genetic inheritability of MS severity may be more closely linked to the intensity of neuroinflammation than to tissue resilience.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Nataf, S., Guillen, M., & Pays, L. (2024). The immunometabolic gene N-acetylglucosamine kinase is uniquely involved in the heritability of multiple sclerosis severity. International Journal of Molecular Sciences, 25(7), 3803.
