Organellar crosstalk as a potential therapeutic target for rare neurodegenerative diseases

Abstract

Organellar crosstalk has gained significant interest due to its essential role in maintaining cellular homeostasis and normal function. Conversely, disruptions in organelles and their interactions are increasingly recognized as key contributors to the pathogenesis of numerous diseases. Rare neurodegenerative diseases, such as Gaucher disease (GD) and X-linked adrenoleukodystrophy (ALD), are caused by inherited mutations that disrupt critical metabolic pathways. Genetic variants encoding key proteins involved in these pathways result in the excessive accumulation of corresponding substrates, which subsequently trigger organellar crosstalk dysfunction, often involving mitochondria, lysosomes, endoplasmic reticulum (ER), or peroxisomes. To date, the specific mechanisms underlying organellar interactions and their roles in the pathophysiology of these respective diseases are not fully elucidated, an area that continues to be actively studied. Understanding these mechanisms could reveal novel pathways or targets for future therapeutic development. Furthermore, the severity of these rare neurodegenerative diseases and the lack of effective treatments for patients underscore the urgency for thorough investigations into organellar crosstalk. This review provides an overview of the crosstalk between mitochondria, lysosomes, the ER, and peroxisomes in lysosomal diseases, such as GD, and peroxisomal disorders, including ALD. Additionally, we explore potential therapeutic strategies targeting these interconnected pathways.