Lysosomal dysfunction has been implicated in many neurodegenerative diseases, including adult onset Alzheimer's and Parkinson's diseases. Several lines of evidence point to lysosomal dysfunction as a critical disease mechanism in frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U)-the most prevalent early onset dementia after Alzheimer's disease. The haplo- insufficiency of the Progranulin (PGRN) gene has been identified as a major cause of FTLD-U, and patients with homozygous PGRN mutations develop neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder. This suggests that PGRN plays a central role in regulating lysosomal function. Other genes mutated in FTLD-U-VCP/p97 and CHMP2B-also regulate endolysosomal trafficking. Further, TMEM106B, a newly identified genetic risk factor for FTLD-U with PGRN mutations, is a lysosomal membrane protein, and increased TMEM106B levels result in lysosomal dysfunction and increased risk for FTLD-U. Our research will examine the physiological functions of TMEM106B in lysosomes and their role in neurodegeneration.
In Aim1, we will use molecular and cell biological approaches to determine how TMEM106B regulates lysosomal activities and lysosomal dynamics. Potential TMEM106B binding partners will also be tested for their function in lysosomes.
In Aim2, we will probe cellular mechanisms that regulate TMEM106B levels and function. In particular, our research will examine the role of regulated intramembrane proteolysis (RIP) and ubiquitination.
In Aim3, we will compare the in vitro and in vivo phenotypes of elevated TMEM106B levels in wild type and PGRN deficient conditions using virus mediated gene delivery to mimic FTLD-U cases. We will also explore the effect of TMEM106B on PGRN metabolism. These proposed studies will shed light on TMEM106B function in lysosomes and cellular pathways that regulate TMEM106B. We hope this research will illustrate the interaction between TMEM106B and PGRN in FTLD-U and provide the foundation for FTLD-U therapeutics. Importantly, this work will also generate broader insights into the regulation of lysosomal function that may be applied in a variety of other neurodegenerative diseases.

Public Health Relevance

We aim to determine the physiological functions of TMEM106B, a newly identified risk factor for Frontotemporal Lobar Degeneration with protein aggregates containing TDP-43 (FTLD-U). Function of TMEM106B in the lysosomes, regulation of TMEM106B by cellular pathways and the interaction between TMEM106B and Progranulin, the main gene mutated in FTLD-U, will be studied.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Sutherland, Margaret L
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Cornell University
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Nicholson, Alexandra M; Zhou, Xiaolai; Perkerson, Ralph B et al. (2018) Loss of Tmem106b is unable to ameliorate frontotemporal dementia-like phenotypes in an AAV mouse model of C9ORF72-repeat induced toxicity. Acta Neuropathol Commun 6:42
Paushter, Daniel H; Du, Huan; Feng, Tuancheng et al. (2018) The lysosomal function of progranulin, a guardian against neurodegeneration. Acta Neuropathol 136:1-17
Zhou, Xiaolai; Sullivan, Peter M; Paushter, Daniel H et al. (2018) The Interaction Between Progranulin with Sortilin and the Lysosome. Methods Mol Biol 1806:269-288
Zhou, Xiaolai; Paushter, Daniel H; Feng, Tuancheng et al. (2017) Lysosomal processing of progranulin. Mol Neurodegener 12:62
Zhou, Xiaolai; Sullivan, Peter M; Sun, Lirong et al. (2017) The interaction between progranulin and prosaposin is mediated by granulins and the linker region between saposin B and C. J Neurochem 143:236-243
Zhou, Xiaolai; Paushter, Daniel H; Feng, Tuancheng et al. (2017) Regulation of cathepsin D activity by the FTLD protein progranulin. Acta Neuropathol 134:151-153
Zhou, Xiaolai; Sun, Lirong; Brady, Owen Adam et al. (2017) Elevated TMEM106B levels exaggerate lipofuscin accumulation and lysosomal dysfunction in aged mice with progranulin deficiency. Acta Neuropathol Commun 5:9
Zhou, Xiaolai; Sun, Lirong; Bracko, Oliver et al. (2017) Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations. Nat Commun 8:15277
Sullivan, Peter M; Zhou, Xiaolai; Robins, Adam M et al. (2016) The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway. Acta Neuropathol Commun 4:51
Zhou, Xiaolai; Sun, Lirong; Bastos de Oliveira, Francisco et al. (2015) Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin. J Cell Biol 210:991-1002

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