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What we know about TMEM106B in neurodegeneration

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Abstract

Frontotemporal lobar degeneration is a neurodegenerative disorder affecting over 50,000 people in the United States alone. The most common pathological subtype of FTLD is the presence of ubiquitinated TAR DNA binding protein 43 (TDP-43) accumulations in frontal and temporal brain regions at autopsy. While some cases of FTLD-TDP can be attributed to the inheritance of disease-causing mutations, the majority of cases arise with no known genetic cause. In 2010, the first genome-wide association study was conducted in patients with FTLD-TDP to determine potential genetic risk factors for this homogenous subgroup of dementia patients, leading to the identification of the TMEM106B locus on chromosome 7. In this manuscript, we review the initial discovery and replication studies describing TMEM106B variants as disease risk factors and modifiers in TDP-43 proteinopathies, such as FTLD-TDP caused by progranulin (GRN) or chromosome 9 open reading frame 72 (C9orf72) mutations, as well as Alzheimer’s disease and hippocampal sclerosis. We further summarize what is currently known about the previously uncharacterized TMEM106B protein and its role as a potential regulator of lysosomal function, and we discuss how modifying TMEM106B levels might uncover promising therapeutic strategies for individuals suffering from TDP-43 proteinopathy.

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Acknowledgments

Rosa Rademakers is funded by National Institutes of Health Grants P50 AG016574, P50 NS072187, R01 NS080882 and R01 NS076471, the ALS Therapy Alliance, and the Consortium for Frontotemporal Dementia. Alexandra Nicholson is funded the Mayo Clinic Edward C. Kendall Research Fellowship. Images of TMEM106B neuronal staining are courtesy of Dr. Dennis Dickson.

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  1. Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Alexandra M. Nicholson & Rosa Rademakers

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Nicholson, A.M., Rademakers, R. What we know about TMEM106B in neurodegeneration. Acta Neuropathol 132, 639–651 (2016). https://doi.org/10.1007/s00401-016-1610-9

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