TMEM106B Puncta Is Increased in Multiple Sclerosis Plaques, and Reduced Protein in Mice Results in Delayed Lipid Clearance Following CNS Injury

Abstract

During inflammatory, demyelinating diseases such as multiple sclerosis (MS), inflammation and axonal damage are prevalent early in the course. Axonal damage includes swelling, defects in transport, and failure to clear damaged intracellular proteins, all of which affect recovery and compromise neuronal integrity. The clearance of damaged cell components is important to maintain normal turnover and restore homeostasis. In this study, we used mass spectrometry to identify insoluble proteins within high-speed/mercaptoethanol/sarcosyl-insoluble pellets from purified white matter plaques isolated from the brains of individuals with relapsing–remitting MS (RRMS). We determined that the transmembrane protein 106B (TMEM106B), normally lysosome-associated, is insoluble in RRMS plaques relative to normal-appearing white matter from individuals with Alzheimer’s disease and non-neurologic controls. Relative to wild-type mice, hypomorphic mice with a reduction in TMEM106B have increased axonal damage and lipid droplet accumulation in the spinal cord following myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis. Additionally, the corpora callosa from cuprizone-challenged hypomorphic mice fail to clear lipid droplets efficiently during remyelination, suggesting that when TMEM106B is compromised, protein and lipid clearance by the lysosome is delayed. As TMEM106B contains putative lipid- and LC3-binding sites, further exploration of these sites is warranted.

TMEM106B reduction does not rescue GRN deficiency in iPSC-derived human microglia and mouse models

“…Insoluble TMEM106B protein was similarly increased in MS plaques compared to controls. 51 While TMEM106B aggregates could impact neuronal cell health, aggregation of TMEM106B could result in loss of function of wild-type TMEM106B protein, leading to altered lysosomal activity and lipid formation across cell types, as modeled in mouse KOs in this study. Future studies investigating the impact of TMEM106B snps on TMEM106B biology as well as novel approaches of targeting TMEM106B fibrils for the treatment of neurodegenerative disease are warranted.…”

“…While reduction of normal TMEM106B seems unlikely to be therapeutic for FTD- GRN , our preclinical data are helpful in interpreting the role of TMEM106B in FTD and other disorders where lysosomal dysfunction, lipid dysregulation, and immune cell activation are key features. 47 , 48 , 49 , 50 , 51 A recurrent de novo genetic mutation in TMEM106B has been associated with hypomyelinating leukodystrophy. 48 Yang et al.…”