Elevated TMEM106B levels exaggerate lipofuscin accumulation and lysosomal dysfunction in aged mice with progranulin deficiency

Mutations resulting in haploinsufficiency of progranulin (PGRN) cause frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP), a devastating neurodegenerative disease. Accumulating evidence suggest a crucial role of progranulin in maintaining proper lysosomal function during agi...

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Bibliographic Details
Published in:Acta neuropathologica communications 2017-01, Vol.5 (1), p.9-9, Article 9
Main Authors: Zhou, Xiaolai, Sun, Lirong, Brady, Owen Adam, Murphy, Kira A, Hu, Fenghua
Format: Article
Language:English
Subjects:
Aging - metabolism
Aging - pathology
Animals
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism
Cerebral Cortex - metabolism
Cerebral Cortex - pathology
Complications and side effects
Disease Models, Animal
Frontotemporal Lobar Degeneration - metabolism
Frontotemporal Lobar Degeneration - pathology
Gene Expression
Genetic aspects
Genetically modified mice
Humans
Inborn errors of metabolism
Intercellular Signaling Peptides and Proteins - deficiency
Intercellular Signaling Peptides and Proteins - genetics
Lipofuscin - metabolism
Lysosomes - metabolism
Lysosomes - pathology
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice, Inbred C57BL
Mice, Transgenic
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Neurodegenerative diseases
Promoter Regions, Genetic
Risk factors
RNA, Messenger - metabolism
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Summary:Mutations resulting in haploinsufficiency of progranulin (PGRN) cause frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP), a devastating neurodegenerative disease. Accumulating evidence suggest a crucial role of progranulin in maintaining proper lysosomal function during aging. TMEM106B has been identified as a risk factor for frontotemporal lobar degeneration with progranulin mutations and elevated mRNA and protein levels of TMEM106B are associated with increased risk for frontotemporal lobar degeneration. Increased levels of TMEM106B alter lysosomal morphology and interfere with lysosomal degradation. However, how progranulin and TMEM106B interact to regulate lysosomal function and frontotemporal lobar degeneration (FTLD) disease progression is still unclear. Here we report that progranulin deficiency leads to increased TMEM106B protein levels in the mouse cortex with aging. To mimic elevated levels of TMEM106B in frontotemporal lobar degeneration (FTLD) cases, we generated transgenic mice expressing TMEM106B under the neuronal specific promoter, CamKII. Surprisingly, we found that the total protein levels of TMEM106B are not altered despite the expression of the TMEM106B transgene at mRNA and protein levels, suggesting a tight regulation of TMEM106B protein levels in the mouse brain. However, progranulin deficiency results in accumulation of TMEM106B protein from the transgene expression during aging, which is accompanied by exaggerated lysosomal abnormalities and increased lipofuscin accumulation. In summary, our mouse model nicely recapitulates the interaction between progranulin and TMEM106B in human patients and supports a critical role of lysosomal dysfunction in the frontotemporal lobar degeneration (FTLD) disease progression.
ISSN:2051-5960
2051-5960
DOI:10.1186/s40478-017-0412-1