Decoding Early Neurodegeneration in Progressive Multiple Sclerosis: A New Avenue for Therapeutic Intervention

Progressive multiple sclerosis (MS) represents a significant clinical challenge, as the transition from the relapsing-remitting phase to secondary progressive MS (SPMS) marks a phase where neurodegeneration takes precedence. Unfortunately, this phase of the disease often proves unresponsive to current treatment modalities, making understanding its underlying mechanisms critical for future therapeutic development.

In this study, Kaufmann et al. applied advanced techniques such as spatial transcriptomics and proteomics on postmortem brain tissue samples from patients with progressive MS. Their goal was to decipher the complex cellular and molecular dynamics involved in neurodegeneration, potentially offering novel targets for therapeutic intervention.

Decoding the Molecular Landscape of Progressive MS
Using spatial transcriptomics, the researchers mapped the expression of thousands of genes across specific regions of the cortex in MS patient brains. This allowed them to visualize how neurodegenerative processes unfold spatially within the brain. In this study, brain tissue from 13 patients with progressive MS and five control cases was analyzed.

Their findings demonstrated a clear reduction in the signature of intact neurons in the cortical gray matter of MS patients, signifying a shift towards a neurodegenerative state. The use of spatial transcriptomics helped the researchers pinpoint regions of the brain that still contained intact neurons compared to areas with extensive neuronal loss.

Multicellular Mechanisms Drive Neurodegeneration
One of the key discoveries of this study was the identification of multicellular mechanisms involved in neurodegeneration. The authors found that the neurodegenerative processes in progressive MS are not driven by a single cell type but involve complex interactions between neurons, microglia, astrocytes, and oligodendrocytes.

Through gene coexpression network analysis, they identified specific gene modules associated with biological processes such as synaptic communication, synaptic plasticity, and myelination, which were progressively downregulated as neurodegeneration advanced. Interestingly, while inflammatory pathways were increasingly upregulated, the study highlighted that neurodegeneration occurs despite active myelination attempts by oligodendrocytes. This suggests that while the brain may attempt to repair itself through remyelination, it is ultimately overwhelmed by the neurodegenerative process.

Proteomics Reveals Molecular Concordance
By applying high-sensitivity proteomics, the researchers validated their findings at the protein level. They discovered that several of the gene modules identified through transcriptomics were also present at the protein level, further confirming their relevance to neurodegenerative pathways.

One of the most striking results was the concordance between transcriptomic and proteomic data in identifying the early-stage molecular changes in progressive MS. Specifically, they observed that synaptic plasticity and neuronal projection pathways were disrupted early in the disease process, even before extensive inflammation took hold.

Trophic Factor Deprivation and Inflammatory Signals
A particularly novel aspect of the study was its focus on ligand-receptor interactions that govern the communication between cells. These interactions revealed key insights into the early stages of MS neurodegeneration. The researchers identified a network of trophic factor signaling, which supports neuronal survival, and found that this was significantly disrupted in the brains of MS patients. Trophic factors such as FGF, VEGF, and PSAP-GPR37L1 were downregulated, while compensatory signals rose in early degenerative stages but failed to counterbalance the neurodegenerative processes.

Simultaneously, the study identified pro-inflammatory and anti-inflammatory ligand-receptor interactions. For example, interactions such as GAS6-TYRO3, which have anti-inflammatory properties, were downregulated in regions of neurodegeneration. In contrast, pro-inflammatory signals like C3-C3AR1 were increasingly upregulated as neurodegeneration progressed, fueling the chronic inflammation seen in MS brains.

Validating Mechanisms in Animal Models
To ensure that their findings had therapeutic relevance, the authors explored how the identified ligand-receptor interactions function in animal models. They found that genes involved in the identified pathways also play key roles in various CNS disease models, such as Alzheimer’s and Parkinson’s disease. This provides strong evidence that the identified molecular pathways in MS are not only involved in neurodegeneration but may also be critical targets for intervention across other neurodegenerative conditions.

Implications for Drug Development
The findings from this study offer a new framework for developing treatments that target the early stages of neurodegeneration in progressive MS. By focusing on the trophic and anti-inflammatory signaling pathways, future therapies could aim to preserve neuronal function and prevent the progression of neurodegeneration before it becomes irreversible.

The researchers also emphasized the importance of identifying drug targets that are specific to the central nervous system (CNS). For example, receptors like GPR37L1, TYRO3, and SIRPA were identified as potential drug targets due to their CNS specificity and their broad roles in neuroprotective and anti-inflammatory processes.

Conclusion
This study provides a comprehensive view of the early neurodegenerative pathways in progressive MS, highlighting the complex interplay between neurons and glial cells, as well as the critical role of ligand-receptor interactions in driving disease progression. By identifying specific molecular targets involved in trophic support and inflammation, the findings lay the groundwork for the development of novel therapies aimed at halting or even reversing the neurodegenerative process in MS.

References:
Kaufmann, M., Schaupp, AL., Sun, R. et al. Identification of early neurodegenerative pathways in progressive multiple sclerosis. Nat Neurosci 25, 944–955 (2022).