9.B.23. The TMEM106B (TMEM106B) Family TMEM106B
TMEM106B variants are genetically associated with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), and are considered a major risk factor for this disease. TMEM106B may also be involved in other pathologies such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Schwenk et al. 2014 combined loss-of-function experiments, live imaging and proteomics to unveil the physiological roles played by TMEM106B and its binding partner MAP6 in lysosomal function and transport. Neuronal TMEM106B plays a central role in regulating lysosomal size, motility and responsiveness to stress (Stagi et al. 2014). Single-nucleotide polymorphisms: rs5848 (GRN), rs1990622 (TMEM106B), and rs704180 (ABCC9) are associated with hippocampal sclerosis of aging (HS-Aging), a common high-morbidity neurodegenerative condition in elderly persons (Nelson et al. 2015). The up-regulation of TMEM106B may increase the risk of FTLD by directly causing neurotoxicity and a pathological phenotype linked to FTLD-TDP (Suzuki and Matsuoka 2016). Nicholson and Rademakers 2016 summarized what was known about TMEM106B and its role as a potential regulator of lysosomal function.