Unraveling the Metabolic Roots of Primary Progressive Multiple Sclerosis: The Genetic-Epigenetic Interplay at 1q21.1

Primary Progressive Multiple Sclerosis (PPMS) represents one of the most challenging forms of Multiple Sclerosis (MS) due to its relentless progression and limited therapeutic options. Unlike the more common relapsing-remitting MS (RRMS), PPMS is characterized by a gradual worsening of symptoms from the onset, with no clear relapses or remissions. This article delves into the recent findings from a study published in Nature Communications that uncovers a complex genetic-epigenetic interplay at the 1q21.1 locus, which contributes to the vulnerability to PPMS through its effects on metabolism and neuronal function.

Hypermethylation at 1q21.1 Locus and Its Implications
The study identified a differentially methylated region (DMR) at the 1q21.1 locus that is specifically hypermethylated in PPMS patients. This hypermethylation was linked to genetic variations at the same locus, which influence the expression of nearby genes, particularly CHD1L and PRKAB2, in the brain. These genes are crucial for neuronal development and function, with CHD1L being involved in chromatin remodeling during DNA repair, and PRKAB2 playing a role in energy metabolism through the regulation of AMP-activated protein kinase (AMPK).

Metabolic Dysfunction in PPMS
The study highlights the significant role of metabolic processes in the pathogenesis of PPMS. PRKAB2, a gene regulated by methylation at the 1q21.1 locus, is essential for cellular energy metabolism. The AMP-activated protein kinase (AMPK) pathway, in which PRKAB2 is involved, is a key regulator of energy homeostasis in neurons. Dysregulation of this pathway can lead to impaired energy metabolism, contributing to the neurodegenerative processes observed in PPMS. This finding suggests that metabolic dysfunction, driven by genetic and epigenetic alterations, may be a central feature of PPMS, distinguishing it from other forms of MS.

Genetic Control of Methylation and Its Impact on Gene Expression
The research further demonstrated that the hypermethylation observed in PPMS is under strong genetic control. Several single nucleotide polymorphisms (SNPs) within the 1q21.1 locus were found to correlate with methylation levels at the DMR. These SNPs not only influenced methylation but also affected the expression of CHD1L and PRKAB2 in the brain. Importantly, variants associated with higher methylation levels were linked to an increased risk of PPMS, suggesting that these genetic variations may predispose individuals to the disease by altering metabolic and neuronal gene expression.

Functional Consequences of CHD1L Dysregulation
The study employed various in vitro and in vivo models to explore the functional impact of CHD1L dysregulation. Knockdown of CHD1L in human iPSC-derived neurons and knockout of its ortholog in zebrafish led to significant developmental and functional deficits in neurons. These findings underscore the importance of CHD1L in maintaining neuronal integrity and suggest that its dysregulation may contribute to the neurodegenerative aspects of PPMS. The connection between CHD1L and metabolic processes is particularly intriguing, as it provides a potential link between genetic susceptibility, epigenetic regulation, and the metabolic disturbances observed in PPMS.

Potential Therapeutic Implications
The identification of a genetic-epigenetic-metabolic axis in PPMS opens up new avenues for therapeutic intervention. Targeting the metabolic pathways regulated by genes like PRKAB2 and CHD1L could potentially mitigate the progression of PPMS. Moreover, epigenetic therapies aimed at modifying DNA methylation patterns at the 1q21.1 locus could restore normal gene expression and metabolic function in affected individuals.

Conclusion
This study sheds light on the intricate interplay between genetics, epigenetics, and metabolism in the pathogenesis of PPMS. The findings suggest that metabolic dysfunction, driven by genetically controlled epigenetic changes, plays a pivotal role in the disease. By unraveling these complex mechanisms, the research provides a foundation for developing targeted therapies that address the metabolic disturbances underlying PPMS, offering hope for improved treatment strategies in the future.

References:
Pahlevan Kakhki, M., Giordano, A., Starvaggi Cucuzza, C. et al. A genetic-epigenetic interplay at 1q21.1 locus underlies CHD1L-mediated vulnerability to primary progressive multiple sclerosis. Nat Commun 15, 6419 (2024).