The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons

Lüningschrör, Patrick; Werner, Georg; Stroobants, Stijn; Kakuta, Soichiro; Dombert, Benjamin; Sinske, Daniela; Wanner, Renate; Lüllmann‐Rauch, Renate; Wefers, Benedikt; Wurst, Wolfgang; D’Hooge, Rudi; Uchiyama, Yasuo; Sendtner, Michael; Haass, Christian; Säftig, Paul; Knöll, Bernd; Capell, Anja; Damme, Markus

doi:10.1016/j.celrep.2020.02.060

Cited by 54 publications

(103 citation statements)

References 46 publications

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“…We have detected the accumulation of p62 and ubiquitinated proteins in the brain and spinal cord lysates of 16‐month‐old TMEM106B‐deficient mice (Fig C–F), indicating that lysosomal dysfunction caused by the loss of TMEM106B leads to autophagy defects during aging. Similar phenotypes have been reported in a recently published study (Luningschror et al , ), although at a much younger age.…”

Section: Discussionsupporting

confidence: 90%

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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Section: Discussionsupporting

confidence: 90%

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

et al. 2020

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“…The top hit of the SARS-CoV-2 screen was TMEM106B, a poorly characterized lysosomal transmembrane protein linked to frontotemporal dementia ( Fig. 1b ) 48 . Deletions in TMEM106B caused defects in lysosome trafficking, impaired acidification and reduced levels of lysosomal enzymes but its precise molecular function remains enigmatic 48 , 49 .…”

Section: Resultsmentioning

confidence: 99%

“…1b) . Deletions in TMEM106B caused defects in lysosome trafficking, impaired acidification and reduced levels of lysosomal enzymes but its precise molecular function remains enigmatic 48,49 .…”

Section: Crispr Knockout Screens Identify Common and Virus-specific Cmentioning

confidence: 99%

Functional genomic screens identify human host factors for SARS-CoV-2 and common cold coronaviruses

Wang

Simoneau

Kulsuptrakul

et al. 2020

Preprint

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The Coronaviridae are a family of viruses that causes disease in humans ranging from mild respiratory infection to potentially lethal acute respiratory distress syndrome. Finding host factors that are common to multiple coronaviruses could facilitate the development of therapies to combat current and future coronavirus pandemics. Here, we conducted parallel genome-wide CRISPR screens in cells infected by SARS-CoV-2 as well as two seasonally circulating common cold coronaviruses, OC43 and 229E. This approach correctly identified the distinct viral entry factors ACE2 (for SARS-CoV-2), aminopeptidase N (for 229E) and glycosaminoglycans (for OC43). Additionally, we discovered phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis as critical host pathways supporting infection by all three coronaviruses. By contrast, the lysosomal protein TMEM106B appeared unique to SARS-CoV-2 infection. Pharmacological inhibition of phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis reduced replication of all three coronaviruses. These findings offer important insights for the understanding of the coronavirus life cycle as well as the potential development of host-directed therapies.

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“…To monitor the autophagic flux in cultured Schwann cells, the cells were transduced with a lentiviral vector expressing mRFP-GFP-LC3. This tandem reporter is a well-established tool enabling the discrimination between autophagosomes and autolysosomes (Klionsky et al, 2016 ; Lüningschrör et al, 2017 , 2020 ). Upon fusion of an autophagosome with a lysosome, the GFP signal is quenched due to the pH drop, whereas the RFP signal remains.…”

Section: Methodsmentioning

confidence: 99%

Absence of Plekhg5 Results in Myelin Infoldings Corresponding to an Impaired Schwann Cell Autophagy, and a Reduced T-Cell Infiltration Into Peripheral Nerves

Lüningschrör

Slotta

Heimann

et al. 2020

Front. Cell. Neurosci.

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Inflammation and dysregulation of the immune system are hallmarks of several neurodegenerative diseases. An activated immune response is considered to be the cause of myelin breakdown in demyelinating disorders. In the peripheral nervous system (PNS), myelin can be degraded in an autophagy-dependent manner directly by Schwann cells or by macrophages, which are modulated by T-lymphocytes. Here, we show that the NF-κB activator Pleckstrin homology containing family member 5 (Plekhg5) is involved in the regulation of both Schwann cell autophagy and recruitment of T-lymphocytes in peripheral nerves during motoneuron disease. Plekhg5-deficient mice show defective axon/Schwann cell units characterized by myelin infoldings in peripheral nerves. Even at late stages, Plekhg5-deficient mice do not show any signs of demyelination and inflammation. Using RNAseq, we identified a transcriptional signature for an impaired immune response in sciatic nerves, which manifested in a reduced number of CD4 + and CD8 + T-cells. These findings identify Plekhg5 as a promising target to impede myelin breakdown in demyelinating PNS disorders.

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The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons

Cited by 54 publications

References 46 publications

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

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

Functional genomic screens identify human host factors for SARS-CoV-2 and common cold coronaviruses

Absence of Plekhg5 Results in Myelin Infoldings Corresponding to an Impaired Schwann Cell Autophagy, and a Reduced T-Cell Infiltration Into Peripheral Nerves

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