Physiological and pathological functions of TMEM106B in neurodegenerative diseases

Abstract

As an integral lysosomal transmembrane protein, transmembrane protein 106B (TMEM106B) regulates several aspects of lysosomal function and is associated with neurodegenerative diseases. The TMEM106B gene mutations lead to lysosomal dysfunction and accelerate the pathological progression of Neurodegenerative diseases. Yet, the precise mechanism of TMEM106B in Neurodegenerative diseases remains unclear. Recently, different research teams discovered that TMEM106B is an amyloid protein and the C-terminal domain of TMEM106B forms amyloid fibrils in various Neurodegenerative diseases and normally elderly individuals. In this review, we discussed the physiological functions of TMEM106B. We also included TMEM106B gene mutations that cause neurodegenerative diseases. Finally, we summarized the identification and cryo-electronic microscopic structure of TMEM106B fibrils, and discussed the promising therapeutic strategies aimed at TMEM106B fibrils and the future directions for TMEM106B research in neurodegenerative diseases.

Keywords: Amyloid fibrils; Lysosome; Neurodegenerative diseases; Neurotherapy; Transmembrane protein 106B.

Fig. 1

Structure, physiological and pathologic function of TMEM106B. ① TMEM106B is a type II transmembrane protein located on late endosome and lysosome, with its N-terminus facing the cytosol and C-terminus facing the lysosome lumen. TMEM106B consists of 274 residues and three structural domains. This C-terminal fragment (118–274 residue) contains five important N-glycosylation sites (N145, N151, N164, N183, N256). TMEM106B is processed into a N-terminal fragment (NTF) by lysosomal proteases, which is further cleaved by SPPL2a through intramembrane proteolysis to generate intracellular cytosolic domain. ② TMEM106B SNPs and mutations lead to TMEM106B abnormal expression and dysfunction in morphology, transportation, acidification and maturation of lysosomes. TMEM106B fragment may form fibrils after cleavage. ③Lysosomal activity is modulated by intraluminal pH. The interaction between TMEM106B and v-ATPase controls the acidification of lysosomes. TMEM106B knockdown results in less efficient fusion with autophagosome, poor protein degradation efficiency, and insufficient acidification. TMEM106B also regulates lysosomal trafficking in neurons. In dendrites, TMEM106B interacts with MAP6 to restrict retrograde transport of lysosomes. Loss of TMEM106B leads to the formation of LAMP1-positive lysosomal vacuoles at the axon initial segment region. This is partly due to increased retrograde transport of lysosomes along axons. TMEM106B further activates TFEB-dependent lysosome biogenesis. Endosome and lysosome fusion are also mediated by TMEM106B