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Loss of TMEM 106B and PGRN leads to severe lysosomal abnormalities and neurodegeneration in mice
Author(s) -
Feng Tuancheng,
Mai Shuyi,
Roscoe Jenn Marie,
Sheng Rory R,
Ullah Mohammed,
Zhang Junke,
Katz Isabel Iscol,
Yu Haiyuan,
Xiong Wenjun,
Hu Fenghua
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202050219
Subject(s) - frontotemporal lobar degeneration , haploinsufficiency , lysosome , neurodegeneration , microglia , microbiology and biotechnology , biology , pathogenesis , axon , axoplasmic transport , phenotype , neuroscience , immunology , pathology , medicine , frontotemporal dementia , inflammation , dementia , genetics , gene , disease , biochemistry , enzyme
Haploinsufficiency of progranulin ( PGRN ) is a leading cause of frontotemporal lobar degeneration ( FTLD ). Loss of PGRN leads to lysosome dysfunction during aging. TMEM 106B , a gene encoding a lysosomal membrane protein, is the main risk factor for FTLD with PGRN haploinsufficiency. But how TMEM 106B affects FTLD disease progression remains to be determined. Here, we report that TMEM 106B 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 TMEM 106B 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 TMEM 106B 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 TMEM 106B in the lysosome, in brain aging, and in FTLD pathogenesis.