Novel Mechanistic Roles for TMEM106B in Regulating Lysosomal Inter-organelle Contact Sites and Misregulation in Frontotemporal Dementia
Anh M. Ly1, Yvette C. Wong2
1Northwestern University Interdepartmental Neuroscience (NUIN), 2Department of Neurology, Northwestern University Feinberg School of Medicine, Northwestern University
Objective:
This study examines novel lysosomal functions of TMEM106B in physiological and pathological conditions and its contribution to Frontotemporal Dementia.
Background:
TMEM106B is an endo-lysosomal transmembrane protein known to be a risk factor for several neurological diseases, including frontal temporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Frontal temporal lobar degeneration is the most common early age of onset dementia. Previous studies revealed TMEM106B loss-of-function as a cause for lysosomal biogenesis impairment, which further contributes to the molecular pathomechanisms of dysfunctional lysosome trafficking in disease. However, there is still very little known about the physiological functions of TMEM106B and its variants in the lysosome and how TMEM106B is associated with a wide range of neurodegenerative diseases at the molecular level. Inter-organelle contact sites are important hubs for organelles such as lysosomes to crosstalk with one another, but how TMEM106B regulates lysosomal contact sites has never been studied.
Design/Methods:
Using Super-Resolution live microscopy, we modulated TMEM106B expression and also analyzed the role of its disease-associated variants in human cell lines and examined its effects on lysosomal dynamics, and inter-organelle contact sites between lysosomes and other organelles.
Results:
We found that TMEM106B can regulate lysosomal contact sites with other organelles, and may play a key role in lysosomal contact site tethering, as well as lysosomal functional crosstalk with other organelles at contact sites. These findings have important consequences for understanding the role of TMEM106B in regulating lysosomal function, and also the role of different disease-associated variants in TMEM106B.
Conclusions:
This study suggests that TMEM106B may play a key role in mechanistically modulating lysosomal contact sites, and that misregulation of this pathway contributes to the disease etiology underlying FTLD-TDP. Moreover, targeting this pathway may modulate disease pathology and progression, and help to explain TMEM106B's contribution as a risk factor in FTLD-TDP.
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