What we know about TMEM106B in neurodegeneration

Abstract

Frontotemporal lobar degeneration is a neurodegenerative disorder affecting over 50,000 people in the United States alone. The most common pathological subtype of FTLD is the presence of ubiquitinated TAR DNA binding protein 43 (TDP-43) accumulations in frontal and temporal brain regions at autopsy. While some cases of FTLD-TDP can be attributed to the inheritance of disease-causing mutations, the majority of cases arise with no known genetic cause. In 2010, the first genome-wide association study was conducted in patients with FTLD-TDP to determine potential genetic risk factors for this homogenous subgroup of dementia patients, leading to the identification of the TMEM106B locus on chromosome 7. In this manuscript, we review the initial discovery and replication studies describing TMEM106B variants as disease risk factors and modifiers in TDP-43 proteinopathies, such as FTLD-TDP caused by progranulin (GRN) or chromosome 9 open reading frame 72 (C9orf72) mutations, as well as Alzheimer's disease and hippocampal sclerosis. We further summarize what is currently known about the previously uncharacterized TMEM106B protein and its role as a potential regulator of lysosomal function, and we discuss how modifying TMEM106B levels might uncover promising therapeutic strategies for individuals suffering from TDP-43 proteinopathy.

Keywords: Frontotemporal dementia; Genetic association; Lysosomes; TDP-43; TMEM106B.

Fig. 1

TMEM106B genomic region. Schematic representation of the TMEM106B genomic region on chromosome 7p21. Introns are drawn in blue while exons are depicted in green, with coding regions drawn taller than non-coding regions. The transcription start site located in exon 3 (E3) is represented by an arrow showing transcriptional direction. Selected FTLD-TDP-associated SNPs are marked with an asterisk (*) to denote their relative location within the TMEM106B locus.

Fig. 2

TMEM106B is found in the lysosomal membrane of neurons. (a) Representation of a neuron and various intracellular compartments, including the lysosome. (b) Magnification of the lysosomal membrane in which TMEM106B resides as a type II transmembrane protein, with the relative location of the p.T185S variant and 5 glycosylation sites (N1–N5) depicted in the luminal region. (c–d) Immunohistochemical labeling of TMEM106B in human brain shows a punctate TMEM106B-immunoreactive pattern in pyramidal neurons of the hippocampus (c) and in granular neurons of the dentate gyrus (d).