Loss of TMEM 106B potentiates lysosomal and FTLD ‐like pathology in progranulin‐deficient mice

Abstract

Single nucleotide polymorphisms (SNPs) in TMEM106B encoding the lysosomal type II transmembrane protein 106B increase the risk for frontotemporal lobar degeneration (FTLD) of GRN (progranulin gene) mutation carriers. Currently, it is unclear if progranulin (PGRN) and TMEM106B are synergistically linked and if a gain or a loss of function of TMEM106B is responsible for the increased disease risk of patients with GRN haploinsufficiency. We therefore compare behavioral abnormalities, gene expression patterns, lysosomal activity, and TDP-43 pathology in single and double knockout animals. Grn À/À /Tmem106b À/À mice show a strongly reduced life span and massive motor deficits. Gene expression analysis reveals an upregulation of molecular signature characteristic for disease-associated microglia and autophagy. Dysregulation of maturation of lysosomal proteins as well as an accumulation of ubiquitinated proteins and widespread p62 deposition suggest that proteostasis is impaired. Moreover, while single Grn À/À knockouts only occasionally show TDP-43 pathology, the double knockout mice exhibit deposition of phosphorylated TDP-43. Thus, a loss of function of TMEM106B may enhance the risk for GRN-associated FTLD by reduced protein turnover in the lysosomal/autophagic system.

Loss of Tmem106b exacerbates FTLD pathologies and causes motor deficits in progranulin‐deficient mice

“…Our new mouse model supports a genetic interaction between TMEM106B and FTLD‐ GRN . In contrast to earlier reports, our results and those published independently by two other research teams in this issue of EMBO Reports (Feng et al , ; Werner et al , ) suggest that loss of Tmem106b exacerbates lysosomal and autophagic dysfunction in Grn − / − mice, which we found to lead to enhanced neuroinflammation, myelin, and motor neuron degeneration, ultimately leading to motor deficits and premature death. Together, our data strongly suggest that a complete loss of TMEM106B might not be a desirable therapeutic treatment for FTLD‐ GRN .…”

The Role of Microglia in Inherited White-Matter Disorders and Connections to Frontotemporal Dementia

“…A series of recently published papers have independently converged on the finding that loss of Tmem106b exacerbates a variety of neurodegeneration-associated phenotypes in mice also lacking Grn. [98][99][100][101] Moreover, mice lacking both Tmem106b and Grn displayed exacerbated lysosomal dysfunction as well as signs of myelin damage. Indeed, loss of Tmem106b on a wild-type Grn background is sufficient to produce oligodendroglial and myelination defects, possibly downstream of lysosomal dysfunction.…”

Tweaking Progranulin Expression: Therapeutic Avenues and Opportunities

“…Complete loss of Tmem106b however, was not beneficial in Grn knockout mice models (Feng et al, 2020;Werner et al, 2020;Zhou et al, 2020). Double knockout mice demonstrated worsened neuropathology with increased TDP-43 accumulation, gliosis, and lysosomal dysfunction.…”

“…Double knockout mice demonstrated worsened neuropathology with increased TDP-43 accumulation, gliosis, and lysosomal dysfunction. Additionally, the mice developed motor deficits, a phenotype not present in single knockout models (Feng et al, 2020;Werner et al, 2020;Zhou et al, 2020). In knockout models that retained a low residual expression of Tmem106b, a phenotypic delay was seen with motor deficits emerging 2 months later (Zhou et al, 2020).…”