Genetic Evidence for Endolysosomal Dysfunction in Parkinson's Disease: A Critical Overview

Parkinson's disease (PD) is the second most common neurodegenerative disorder in the aging population, and no disease-modifying therapy has been approved to date. The pathogenesis of PD has been related to many dysfunctional cellular mechanisms, however, most of its monogenic forms are caused by pathogenic variants in genes involved in endolysosomal function (LRRK2, VPS35, VPS13C, and ATP13A2) and synaptic vesicle trafficking (SNCA, RAB39B, SYNJ1, and DNAJC6). Moreover, an extensive search for PD risk variants revealed strong risk variants in several lysosomal genes (e.g., GBA1, SMPD1, TMEM175, and SCARB2) highlighting the key role of lysosomal dysfunction in PD pathogenesis. Furthermore, large genetic studies revealed that PD status is associated with the overall lysosomal genetic burden, namely the cumulative effect of strong and weak risk variants affecting lysosomal genes. In this context, understanding the complex mechanisms of impaired vesicular trafficking and dysfunctional endolysosomes in dopaminergic neurons of PD patients is a fundamental step to identifying precise therapeutic targets and developing effective drugs to modify the neurodegenerative process in PD.

Automated summary

Parkinson's disease is the second most common neurodegenerative disorder among aging individuals and lacks disease-modifying therapy. The pathogenesis of Parkinson's disease involves dysfunction in several cellular mechanisms, with many monogenic forms resulting from pathogenic variants in genes related to endolysosomal function and synaptic vesicle trafficking. Additionally, studies have found a strong association between Parkinson's disease and lysosomal genes, indicating the significant role of lysosomal dysfunction in disease development. Understanding the mechanisms behind impaired vesicular trafficking and dysfunctional endolysosomes in dopaminergic neurons is crucial for identifying therapeutic targets and developing effective drugs for modifying the neurodegenerative process.