Exploring Pro-Inflammatory Immunological Mediators: Unraveling the Mechanisms of Neuroinflammation in Lysosomal Storage Diseases

Abstract

Lysosomal storage diseases are a group of rare and ultra-rare genetic disorders caused by defects in specific genes that result in the accumulation of toxic substances in the lysosome. This excess accumulation of such cellular materials stimulates the activation of immune and neurological cells, leading to neuroinflammation and neurodegeneration in the central and peripheral nervous systems. Examples of lysosomal storage diseases include Gaucher, Fabry, Tay–Sachs, Sandhoff, and Wolman diseases. These diseases are characterized by the accumulation of various substrates, such as glucosylceramide, globotriaosylceramide, ganglioside GM2, sphingomyelin, ceramide, and triglycerides, in the affected cells. The resulting pro-inflammatory environment leads to the generation of pro-inflammatory cytokines, chemokines, growth factors, and several components of complement cascades, which contribute to the progressive neurodegeneration seen in these diseases. In this study, we provide an overview of the genetic defects associated with lysosomal storage diseases and their impact on the induction of neuro-immune inflammation. By understanding the underlying mechanisms behind these diseases, we aim to provide new insights into potential biomarkers and therapeutic targets for monitoring and managing the severity of these diseases. In conclusion, lysosomal storage diseases present a complex challenge for patients and clinicians, but this study offers a comprehensive overview of the impact of these diseases on the central and peripheral nervous systems and provides a foundation for further research into potential treatments.

Uncovering the Lipid Web: Discovering the Multifaceted Roles of Lipids in Human Diseases and Therapeutic Opportunities

“…Lipids, comprising fatty acids, glycerol, and sterols, serve as vital components in cellular structure, energy storage, and signaling. While lipids are essential for maintaining normal bodily functions, disturbances in lipid metabolism can contribute to the pathogenesis of various human diseases, i.e., diabetes [90,91], obesity [92,93], cancer [94][95][96], cardiovascular [97][98][99][100][101], malaria [102,103], epilepsy [104], COVID-19 [105][106][107][108], Alzheimer [109], Parkinson [75,76] and lysosomal storage diseases [58]. Understanding the sophisticated interplay between lipids and human health is crucial for developing effective strategies to combat lipid-related disorders.…”

“…By understanding the specific alterations in lipid metabolism associated with different diseases, studies can develop targeted interventions to restore lipid homeostasis and mitigate disease progression. The potential of modulating lipid metabolism, such as targeting C5a/C5aR1 pathway in PD and lysosomal storage diseases [58,[87][88][89], ACAT1/SOAT1 inhibition in Alzheimer's disease [85], or modifying nutrient availability in cancer cells [70], opens new avenues for therapeutic approaches.…”

“…Obesity is a global health concern characterized by an excess of adipose tissue, predominantly composed of triglycerides. Such adipose tissue accumulation of triglyceride not only contributes to chronic inflammation but also leads to insulin resistance, paving the way for the development of fatty liver diseases, both alcoholic and non-alcoholic in nature, termed non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) [57,58]. The association between obesity, insulin resistance, and altered lipid metabolism extends to type 2 diabetes, the leading cause of death among adults [59][60][61].…”

The inflammatory pathogenetic pathways of Fabry nephropathy

“…Inflammatory pathway activation is also manifested by the presence of complement-activated components C3 and iC3b in the GLA knockout mouse model [13] and in the serum, plasma, and brain of patients with Fabry disease [14] .…”

Examining the Role of a Functional Deficiency of Iron in Lysosomal Storage Disorders with Translational Relevance to Alzheimer’s Disease

“…The range of presentations include early onset and death in early childhood to adult onset with neurological disabilities. Although lysosomal storage diseases result in impaired digestion of substrates, there can be various affected organelles [29] and several associated pathogenic mechanisms, such as inflammation and disrupted proteostasis [30,31]. In addition, multiple cellular processes can be impaired, e.g., autophagy, calcium homeostasis, endocytosis, and synaptic function [32].…”