A role of the frontotemporal lobar degeneration risk factor TMEM106B in myelination

Feng, Tuancheng; Sheng, Rory R; Solé-Domènech, Santiago; Ullah, Mohammed; Zhou, Xiaolai; Mendoza, Christina S.; Enriquez, Laura Camila Martinez; Katz, Isabel Iscol; Paushter, Daniel H.; Sullivan, Peter M.; Wu, Xiaochun; Maxfield, Frederick R.; Hu, Fenghua

doi:10.1093/brain/awaa154

Cited by 33 publications

(57 citation statements)

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“…Among the strongest hits in double knockouts are mostly microglial expressed genes such as Cd68, Trem2, Tyrobp, Apoe, and complement factors but also genes associated with astrocyte activation such as Gfap,Serpina3n,and C4a (Figs 2C and 3C). Additionally, we detect in 4.5-month-old double knockouts reduced gene expression of myelination-associated genes (Fa2h, Mog, Mag, Ugt8a, Mal) and reduced protein levels of MOG and MAP ( Fig EV1) which is in line with recent publications describing myelination deficits upon TMEM106B deficiency or loss of function (Feng et al, 2020b;Ikemoto et al, 2020;Zhou et al, 2020b). Finally, the question arises how PGRN and TMEM106B deficiency results in lysosomal dysfunction affecting mainly microglia, which initiates autophagic cargo protein accumulation and pathological TDP-43 deposition in neurons.…”

Section: Discussionsupporting

confidence: 92%

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

et al. 2020

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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.

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Section: Discussionsupporting

confidence: 92%

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

et al. 2020

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“…To determine the physiological function of TMEM106B, we generated a Tmem106b − / − mouse line using the CRISPR/Cas9 technique (Cong et al , ; Mali et al , ), in which a 341 bp fragment including the start codon was removed using two guide RNAs. Gene editing was verified by sequencing, PCR, and Western blot analysis using antibodies specific to TMEM106B (Feng et al , ). Loss of TMEM106B alone does not result in any obvious behavioral deficits in young mice, except slight motor coordination deficits on balance beams (Feng et al , ).…”

Section: Resultsmentioning

confidence: 99%

“…Gene editing was verified by sequencing, PCR, and Western blot analysis using antibodies specific to TMEM106B (Feng et al , ). Loss of TMEM106B alone does not result in any obvious behavioral deficits in young mice, except slight motor coordination deficits on balance beams (Feng et al , ). A slight increase in GFAP levels, indicating astrocyte activation, as well as subtle changes in the levels of lysosomal proteins were also detected in TMEM106B‐deficient mice(Feng et al , ).…”

Section: Resultsmentioning

confidence: 99%

Loss of TMEM 106B and PGRN leads to severe lysosomal abnormalities and neurodegeneration in mice

et al. 2020

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Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). Loss of PGRN leads to lysosome dysfunction during aging. TMEM106B, a gene encoding a lysosomal membrane protein, is the main risk factor for FTLD with PGRN haploinsufficiency. But how TMEM106B affects FTLD disease progression remains to be determined. Here, we report that TMEM106B deficiency in mice leads to accumulation of lysosome vacuoles at the distal end of the axon initial segment in motor neurons and the development of FTLD-related pathology during aging. Ablation of both PGRN and TMEM106B in mice results in severe neuronal loss and glial activation in the spinal cord, retina, and brain. Enlarged lysosomes are frequently found in both microglia and astrocytes. Loss of both PGRN and TMEM106B results in an increased accumulation of lysosomal vacuoles in the axon initial segment of motor neurons and enhances the manifestation of FTLD phenotypes with a much earlier onset. These results provide novel insights into the role of TMEM106B in the lysosome, in brain aging, and in FTLD pathogenesis.

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“…Indeed, loss of Tmem106b on a wild-type Grn background is sufficient to produce oligodendroglial and myelination defects, possibly downstream of lysosomal dysfunction. 102 , 103 The white-matter abnormalities described in Tmem106b -deficient mice are not surprising given that pathogenic TMEM106B mutations have been identified as a cause of hypomyelinating leukodystrophy. 104 In particular, a recurrent, dominant, and in some cases de novo mutation in TMEM106B has been found to cause a relatively mild form of hypomyelinating leukodystrophy.…”

Section: Progranulin-associated Genes: Role In Disorders Of White Matmentioning

confidence: 99%

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

Sirkis¹,

Bonham²,

Yokoyama³

2021

TACG

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Microglia play a critical but poorly understood role in promoting white-matter homeostasis. In this review, we leverage advances in human genetics and mouse models of leukodystrophies to delineate our current knowledge and identify outstanding questions regarding the impact of microglia on central nervous system white matter. We first focus on the role of pathogenic mutations in genes, such as TREM2, TYROBP, and CSF1R, that cause leukodystrophies in which the primary deficit is thought to originate in microglia. We next discuss recent advances in disorders such as adrenoleukodystrophy and Krabbe disease, in which microglia play an increasingly recognized role. We conclude by reviewing the roles of GRN and related genes, such as TMEM106B, PSAP, and SORT1, that affect microglial biology and associate with several types of disease, including multiple leukodystrophies as well as forms of frontotemporal dementia (FTD) presenting with white-matter abnormalities. Taken together, mouse and human data support the notion that loss of microglia-facilitated white-matter homeostasis plays an important role in the development of leukodystrophies and suggest novel mechanisms contributing to FTD.

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A role of the frontotemporal lobar degeneration risk factor TMEM106B in myelination

Cited by 33 publications

References 50 publications

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

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

Loss of TMEM 106B and PGRN leads to severe lysosomal abnormalities and neurodegeneration in mice

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

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