Good news! Towards defeating those dreaded neurodegenerative diseases!
"... In a new study, ... researchers reveal new insights into this question, finding that the LRRK2 gene can suppress activity in lysosomes, microscopic organelles that play a key role in breaking down and disposing of cellular waste. ...
LRRK2 genes can also reduce activity of macrophages and microglia, specialized cells that act as the body’s scavengers, clearing away misfolded proteins, cell debris, dead cells, and pathogens, the researchers found. In the brain, microglia help protect neurons from threats posed by these excess materials. ...
The loss of such protective functions as a result of LRRK2 genetic mutations could explain the link between LRRK2 and Parkinson’s disease, the researchers say. Furthermore, outside the brain, the suppression of lysosomes by LRRK2 in macrophages may help explain links between LRRK2 and other diseases including leprosy and Crohn’s disease. ...
“LRRK2 acts like a brake on a garbage truck and if the brake is too strong it limits the ability of these scavenger cells to eliminate damaging material,” ..."
From the significance and abstract:
"Significance
This study defines a homeostatic mechanism that allows macrophages and microglia to match the degradative activity of their lysosomes to ongoing changes in cellular demand. It shows that the leucine-rich repeat kinase 2 (LRRK2) protein suppresses lysosome degradative activity by inhibiting the expression and nuclear localization of the MiT-TFE family of transcription factors that control the expression of multiple genes that encode lysosome proteins. It further demonstrates that a Parkinson’s disease mutation that hyperactivates LRRK2 kinase activity limits the degradative activity of lysosomes more strongly. These findings support a model wherein LRRK2 protects cells from excessive lysosome degradative activity and suggest that overactivation of this pathway may increase Parkinson’s disease risk by limiting the degradative activity of lysosomes.
Abstract
Cells maintain optimal levels of lysosome degradative activity to protect against pathogens, clear waste, and generate nutrients. Here, we show that LRRK2, a protein that is tightly linked to Parkinson’s disease, negatively regulates lysosome degradative activity in macrophages and microglia via a transcriptional mechanism. Depletion of LRRK2 and inhibition of LRRK2 kinase activity enhanced lysosomal proteolytic activity and increased the expression of multiple lysosomal hydrolases. Conversely, the kinase hyperactive LRRK2 G2019S Parkinson’s disease mutant suppressed lysosomal degradative activity and gene expression. We identified MiT-TFE transcription factors (TFE3, TFEB, and MITF) as mediators of LRRK2-dependent control of lysosomal gene expression. LRRK2 negatively regulated the abundance and nuclear localization of these transcription factors and their depletion prevented LRRK2-dependent changes in lysosome protein levels. These observations define a role for LRRK2 in controlling lysosome degradative activity and support a model wherein LRRK2 hyperactivity may increase Parkinson’s disease risk by suppressing lysosome degradative activity."
LRRK2 suppresses lysosome degradative activity in macrophages and microglia through MiT-TFE transcription factor inhibition (open access)
Fig. 2 LRRK2 negatively regulates the levels of multiple lysosomal proteins in human iPSC-derived macrophages.
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