Physiological and pathological functions of TMEM106B: a gene associated with brain aging and multiple brain disorders

Abstract

TMEM106B, encoding a lysosome membrane protein, has been recently associated with brain aging, hypomyelinating leukodystrophy and multiple neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). During the past decade, considerable progress has been made towards our understanding of the cellular and physiological functions of TMEM106B. TMEM106B regulates many aspects of lysosomal function, including lysosomal pH, lysosome movement, and lysosome exocytosis. Both an increase and decrease in TMEM106B levels result in lysosomal abnormalities. In mouse models, TMEM106B deficiency leads to lysosome trafficking and myelination defects and FTLD related pathology. In humans, alterations in TMEM106B levels or function are intimately linked to neuronal proportions, brain aging, and brain disorders. Further elucidation of the physiological function of TMEM106B and changes in TMEM106B under pathological conditions will facilitate therapeutic development to treat brain disorders associated with TMEM106B.

Keywords: Aging; FTLD; Lysosome; Myelination; Progranulin; TDP-43; TMEM106B.

Figure 1. TMEM106B genomic structure and variants.

The human TMEM106B gene is comprised of 9 exons. The coding regions are labelled in red. The major SNPs associated with neurodegenerative diseases are indicated. The CTCF binding sites are labelled in blue.

Figure 2. Domain structure and proteolytic processing of TMEM106B protein.

TMEM106B is a type II transmembrane protein localized on lysosome membrane, with its N-terminus facing the cytosol and C-terminus facing lysosomal lumen. The lumenal domain contains five predicted N-glycosylation sites. Heterozygous D252N mutation in TMEM106B is associated with HLD. The T185S variant has been to be protective towards several neurodegenerative diseases. TMEM106B forms homodimers and heterodimers with its homolog TMEM106C. TMEM106B is processed into an N-terminal fragment (NTF) by lysosomal proteases, which is further cleaved by SPPL2a through intramembrane proteolysis to generate intracellular cytosolic domain (ICD).

Figure 3. TMEM106B regulates lysosomal trafficking in neurons.

In dendrites, TMEM106B interacts with MAP6 to restrict retrograde transport of lysosomes. In axons, TMEM106B regulates lysosome transport across the axon initial segment (AIS) region. TMEM106Bdeficiency results in increased retrograde transport of lysosomes in dendrites and reduced dendritic branching in cultured neurons. In mouse models, loss of TMEM106B leads to the formation of LAMP1 positive lysosomal vacuoles at the AIS region in motor neurons and Purkinje neurons. This is partly due to increased retrograde transport of lysosomes along axons. TMEM106B ablation also results in alterations in the myelin sheath along axons.

Figure 4. TMEM106B and myelination.

TMEM106B is highly expressed in oligodendrocytes and is localized in the lysosome in these cells. TMEM106B deficiency in oligodendrocytes results in lysosome clustering near the nucleus and a defect in lysosomal exocytosis, which leads to trafficking defects and decreased cell surface levels of myelin membrane protein, PLP. Additionally, TMEM106B might modulate the endocytic recycling of MOG, a type I transmembrane protein found in the myelin sheath.