Microglial Progranulin: Involvement in Alzheimer's Disease and Neurodegenerative Diseases

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2019 Mar 14

PMID 30862089

Citations 37

Authors

Anarmaa Mendsaikhan

Ikuo Tooyama

Douglas G Walker

Affiliations

Soon will be listed here.

Abstract

Neurodegenerative diseases such as Alzheimer's disease have proven resistant to new treatments. The complexity of neurodegenerative disease mechanisms can be highlighted by accumulating evidence for a role for a growth factor, progranulin (PGRN). PGRN is a glycoprotein encoded by the GRN/Grn gene with multiple cellular functions, including neurotrophic, anti-inflammatory and lysosome regulatory properties. Mutations in the GRN gene can lead to frontotemporal lobar degeneration (FTLD), a cause of dementia, and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Both diseases are associated with loss of PGRN function resulting, amongst other features, in enhanced microglial neuroinflammation and lysosomal dysfunction. PGRN has also been implicated in Alzheimer's disease (AD). Unlike FTLD, increased expression of PGRN occurs in brains of human AD cases and AD model mice, particularly in activated microglia. How microglial PGRN might be involved in AD and other neurodegenerative diseases will be discussed. A unifying feature of PGRN in diseases might be its modulation of lysosomal function in neurons and microglia. Many experimental models have focused on consequences of PGRN gene deletion: however, possible outcomes of increasing PGRN on microglial inflammation and neurodegeneration will be discussed. We will also suggest directions for future studies on PGRN and microglia in relation to neurodegenerative diseases.

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References

Finch N, Carrasquillo M, Baker M, Rutherford N, Coppola G, DeJesus-Hernandez M . TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology. 2010; 76(5):467-74. PMC: 3034409. DOI: 10.1212/WNL.0b013e31820a0e3b. View

Wilke C, Gillardon F, Deuschle C, Hobert M, Jansen I, Metzger F . Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in GRN-Negative Frontotemporal Dementia. Neurodegener Dis. 2016; 17(2-3):83-88. DOI: 10.1159/000448896. View

Chen J, Saito S, Kobayashi N, Sato K, Terashita T, Shimokawa T . Expression patterns in alternative splicing forms of prosaposin mRNA in the rat facial nerve nucleus after facial nerve transection. Neurosci Res. 2007; 60(1):82-94. DOI: 10.1016/j.neures.2007.09.010. View

Lui H, Zhang J, Makinson S, Cahill M, Kelley K, Huang H . Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation. Cell. 2016; 165(4):921-35. PMC: 4860138. DOI: 10.1016/j.cell.2016.04.001. View

Moisse K, Volkening K, Leystra-Lantz C, Welch I, Hill T, Strong M . Divergent patterns of cytosolic TDP-43 and neuronal progranulin expression following axotomy: implications for TDP-43 in the physiological response to neuronal injury. Brain Res. 2008; 1249:202-11. DOI: 10.1016/j.brainres.2008.10.021. View

He Z, Ong C, Halper J, Bateman A . Progranulin is a mediator of the wound response. Nat Med. 2003; 9(2):225-9. DOI: 10.1038/nm816. View

Luo J, Elwood F, Britschgi M, Villeda S, Zhang H, Ding Z . Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival. J Exp Med. 2013; 210(1):157-72. PMC: 3549715. DOI: 10.1084/jem.20120412. View

Minami S, Min S, Krabbe G, Wang C, Zhou Y, Asgarov R . Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models. Nat Med. 2014; 20(10):1157-64. PMC: 4196723. DOI: 10.1038/nm.3672. View

Holler C, Taylor G, Deng Q, Kukar T . Intracellular Proteolysis of Progranulin Generates Stable, Lysosomal Granulins that Are Haploinsufficient in Patients with Frontotemporal Dementia Caused by Mutations. eNeuro. 2017; 4(4). PMC: 5562298. DOI: 10.1523/ENEURO.0100-17.2017. View

10.

He Z, Bateman A . Progranulin gene expression regulates epithelial cell growth and promotes tumor growth in vivo. Cancer Res. 1999; 59(13):3222-9. View

11.

Mackenzie I, Baker M, Pickering-Brown S, Hsiung G, Lindholm C, Dwosh E . The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain. 2006; 129(Pt 11):3081-90. DOI: 10.1093/brain/awl271. View

12.

Van Kampen J, Baranowski D, Kay D . Progranulin gene delivery protects dopaminergic neurons in a mouse model of Parkinson's disease. PLoS One. 2014; 9(5):e97032. PMC: 4013129. DOI: 10.1371/journal.pone.0097032. View

13.

Tanaka Y, Suzuki G, Matsuwaki T, Hosokawa M, Serrano G, Beach T . Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes. Hum Mol Genet. 2017; 26(5):969-988. DOI: 10.1093/hmg/ddx011. View

14.

Uddin M, Al Mamun A, Labu Z, Hidalgo-Lanussa O, Barreto G, Ashraf G . Autophagic dysfunction in Alzheimer's disease: Cellular and molecular mechanistic approaches to halt Alzheimer's pathogenesis. J Cell Physiol. 2018; 234(6):8094-8112. DOI: 10.1002/jcp.27588. View

15.

Tansey M, Romero-Ramos M . Immune system responses in Parkinson's disease: Early and dynamic. Eur J Neurosci. 2018; 49(3):364-383. PMC: 6391192. DOI: 10.1111/ejn.14290. View

16.

Matsuwaki T, Asakura R, Suzuki M, Yamanouchi K, Nishihara M . Age-dependent changes in progranulin expression in the mouse brain. J Reprod Dev. 2010; 57(1):113-9. DOI: 10.1262/jrd.10-116s. View

17.

Salazar D, Butler V, Argouarch A, Hsu T, Mason A, Nakamura A . The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels. J Neurosci. 2015; 35(25):9315-28. PMC: 4478251. DOI: 10.1523/JNEUROSCI.4808-14.2015. View

18.

Kayasuga Y, Chiba S, Suzuki M, Kikusui T, Matsuwaki T, Yamanouchi K . Alteration of behavioural phenotype in mice by targeted disruption of the progranulin gene. Behav Brain Res. 2007; 185(2):110-8. DOI: 10.1016/j.bbr.2007.07.020. View

19.

Jian J, Li G, Hettinghouse A, Liu C . Progranulin: A key player in autoimmune diseases. Cytokine. 2016; 101:48-55. PMC: 5303690. DOI: 10.1016/j.cyto.2016.08.007. View

20.

Ahmed Z, Sheng H, Xu Y, Lin W, Innes A, Gass J . Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. Am J Pathol. 2010; 177(1):311-24. PMC: 2893674. DOI: 10.2353/ajpath.2010.090915. View