Deciphering Gene Expression in Neurodegenerative and Autoimmune Diseases: Pathways to New Therapies

Understanding the gene expression patterns in complex diseases, such as neurodegenerative and autoimmune diseases, is crucial for advancing our knowledge of their pathogenesis and for developing targeted therapies. Recent studies have provided significant insights into these patterns, revealing both similarities and differences between these two groups of diseases.

Gene Expression in Neurodegenerative Diseases

In neurodegenerative diseases, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS), gene expression profiling (GEP) has become an invaluable tool. These studies have consistently revealed dysregulation of genes related to neuroinflammation across different neurodegenerative diseases. For instance, in ALS, GEP studies have implicated the cytoskeleton, inflammation, protein turnover, and RNA splicing. Parkinson's disease GEP studies highlighted the dysfunction of the ubiquitin–proteasome system and mitochondrial function. In Alzheimer's disease, affected pathways identified include neuroinflammation, mitochondrial function, and calcium signaling. These studies suggest that these diseases share common pathways of disease pathogenesis, potentially pointing to overlapping therapeutic targets and biomarkers​​.

Gene Expression in Autoimmune Diseases

Autoimmune diseases, on the other hand, arise from complex interactions between genetic and environmental factors. A study comparing gene expression profiles in peripheral blood mononuclear cells of individuals with different autoimmune diseases (like rheumatoid arthritis, systemic lupus erythematosus, insulin-dependent diabetes mellitus, and multiple sclerosis) to normal individuals revealed a common gene expression profile distinct from the immune profile in all autoimmune individuals, including unaffected first-degree relatives. This suggests that the expression pattern in autoimmunity is independent of the specific autoimmune disease and clinical parameters associated with it​​.

Moreover, recent studies have begun to explore the intersection of neurodegenerative and autoimmune diseases, particularly focusing on genetic and immunological aspects. It's been observed that neurodegenerative diseases often involve immune-related pathways. For example, Alzheimer's disease progression has been linked to the accumulation of B cells and immunoglobulin deposits around amyloid plaques. In Parkinson's disease, the gene LRRK2 is a shared disease risk for Crohn's disease and Parkinson's, indicating a possible overlap in genetic predisposition for neurodegenerative and autoimmune diseases​​.

Multiple Sclerosis: A Case at the Intersection

Multiple Sclerosis (MS) stands as a prime example of the complex interplay between neurodegenerative and autoimmune processes. MS is a neurodegenerative autoimmune disorder that specifically affects the central nervous system (CNS), presenting a unique model for studying the confluence of these two disease categories. The study of MS offers crucial insights into the gene expression patterns and cellular mechanisms that underpin both neurodegenerative and autoimmune diseases.

Recent research has made significant strides in unraveling the complexities of MS. A study utilizing gene expression profiling of microarray dataset GSE38010 identified 58,866 differentially expressed genes (DEGs) in MS patients during active inflammation and late subsided stages. This comprehensive analysis revealed three hub genes (SCN2A, HTR2A, and HCN1) that could serve as potential biomarkers for MS prognosis. Additionally, the expression patterns of HPCA and PLCB1 provided insights into MS progression, indicating their potential utility in predicting the disease's trajectory​​.

The immunological aspect of MS has been increasingly understood through recent studies that explore the role of immune cells at different stages of MS and their interactions with CNS cells. These findings challenge the traditional notion of an antigen-specific cause of MS, highlighting shared functions among distinct immune cell types that drive the disease. Importantly, the differentiation of immune cells into a pathogenic state in MS is potentially reversible, suggesting that therapeutic manipulation could uncouple these disease processes and provide novel treatment targets​​.

Progressive MS, characterized by relentless neurodegeneration, has been the subject of detailed study using spatial transcriptomics and proteomics. This research has identified multicellular mechanisms of MS pathogenesis and traced their origin in relation to spatially distributed stages of neurodegeneration. The study revealed defunct trophic and anti-inflammatory intercellular communications within areas of early neuronal decline. These findings underscore the causal role of identified proteins and provide a new framework for drug development strategies in progressive MS​​.

These insights highlight the importance of exploring gene expression patterns in complex diseases. By understanding the shared and distinct molecular mechanisms underlying these diseases, researchers can develop more effective diagnostic tools and treatments. For instance, identifying common gene expression patterns could lead to the repurposing of existing immunotherapies for neurodegenerative diseases, potentially slowing disease progression​​. Furthermore, the discovery of distinct gene expression profiles in autoimmune diseases suggests the possibility of developing individualized treatments based on genetic predisposition​​.

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