Cellular lysosomal degradative activity is key for healthy cell maintenance. As such, it is unsurprising that changes in the level of this activity are implicated in disease development. A recent study from researchers at Yale University, published in the PNAS, has established a link between suppression of lysosomal activity and mutations in the leucine-rich repeat kinase 2 (LRRK2) gene, which may lead to an increased risk of Parkinson’s disease.
Lysosomes: regulation is vital
Lysosomes play essential roles in the protection of cells against pathogens, clearance of cellular waste and generation of intracellular nutrients. However, tight regulation of their activity is essential for normal cell homeostasis. Links between the dysregulation of lysosomal degradative activity and development of several diseases have been established, but the precise mechanisms involved are still being actively researched.
A key mutation
This study aimed to understand the transcriptional control of lysosomal activity. Researchers identified the LRRK2 gene as a key regulator of this process in macrophages and microglia through negative regulation of the MiT-TFE family of transcription factors. Induction of the functional protein LRRK2 occurs following cellular stress, where it has roles in both lysosomal membrane repair and maintenance of normal lysosomal morphology. Through the negative regulation of MiT-TFE family members, active LRRK2 was found to suppress several protein coding genes including TFE3, TFEB and MITF, leading to diminished lysosomal protein levels and reduced degradative activity. Conversely, loss of LRRK2 resulted in increased lysosomal proteolytic activity and expression of multiple lysosomal hydrolases. Due to this critical role in lysosomal regulation, mutations in LRRK2 have been implicated in development of an autosomal dominant form of Parkinson’s disease, alongside an increased risk of pathogen infection and inflammatory diseases.
Parkinson’s disease treatments and more
Several established Parkinson’s disease mutations have been shown to increase the kinase activity of LRRK2, which alongside hyperactivation mutations in LRRK2 itself, may increase the risk of Parkinson’s disease development through lysosome inhibition. This finding highlights the potential for use of LRRK2 inhibitors in treatment of not only Parkinson’s disease, but other diseases associated with lysosome deficiencies, as LRRK2 is also expressed in a diverse range of non-neuronal cell types. Phase I clinical trials using LRRK2 inhibitors in Parkinson’s disease found they were generally well tolerated. Ongoing phase 3 clinical trials hope to see positive outcomes and determine the use of LRRK2 inhibitors in future disease management.