Progranulin promotes neurite outgrowth and neuronal differentiation by regulating GSK-3β

Abstract

Progranulin (PGRN) has recently emerged as a key player in a subset of frontotemporal dementias (FTD). Numerous mutations in the progranulin gene have been identified in patients with familial or sporadic frontotemporal lobar degeneration (FTLD). In order to understand the molecular mechanisms by which PGRN deficiency leads to FTLD, we examined activity of PGRN in mouse cortical and hippocampal neurons and in human neuroblastoma SH-SY5Y cells. Treatment of mouse neurons with PGRN protein resulted in an increase in neurite outgrowth, supporting the role of PGRN as a neurotrophic factor. PGRN treatment stimulated phosphorylation of glycogen synthase kinase-3 beta (GSK-3β) in cultured neurons. Knockdown of PGRN in SH-SY5Y cells impaired retinoic acid induced differentiation and reduced the level of phosphorylated GSK-3β. PGRN knockdown cells were also more sensitized to staurosporine-induced apoptosis. These results reveal an important role of PGRN in neurite outgrowth and involvement of GSK-3β in mediating PGRN activity. Identification of GSK-3β activation as a downstream event for PGRN signaling provides a mechanistic explanation for PGRN activity in the nervous system. Our work also suggest that loss of axonal growth stimulation during neural injury repair or deficits in axonal repair may contribute to neuronal damage or axonal loss in FTLD associated with PGRN mutations. Finally, our study suggests that modulating GSK-3β or similar signaling events may provide therapeutic benefits for FTLD cases associated with PGRN mutations.

Activity-dependent secretion of progranulin from synapses

“…Previous work has demonstrated an important role for PGRN in promoting neuronal survival and outgrowth, as well as in modulating neuronal connectivity (Gao et al, 2010;Guo et al, 2010;Petkau et al, 2012;Ryan et al, 2009;Tapia et al, 2011;Van Damme et al, 2008). PGRN is normally expressed in a large number of neuronal populations in the adult CNS (Petkau et al, 2010); however, acute and chronic insults to the CNS, including neurodegenerative disorders such as FTD, result in a dramatic upregulation of PGRN in microglia, suggesting that PGRN may play a key role in regulating the neuroinflammatory response Matzilevich et al, 2002).…”

“…PGRN has an important role in regulating neurite outgrowth (Gao et al, 2010;Laird et al, 2010;Ryan et al, 2009;Van Damme et al, 2008), and neuronal activity might be a key factor in modulating the manner in which PGRN exerts its effects on neuronal arborization. For instance, acute increases in BDNF concentration and resulting transient activation of TrkB enhances neurite elongation and spine head enlargement (Ji et al, 2010).…”

Progranulin deficiency induces overactivation of WNT5A expression via TNF-α/NF-κB pathway in peripheral cells from frontotemporal dementia-linked granulin mutation carriers

“…GRN knockdown was achieved using pSUPERIOR RNAi construct as previously described. 42 We designed a sequence of 19 nucleotides targeted against nucleotides 207-226 (#207) of the human GRN messenger RNA (mRNA). The 64 nt short hairpin RNA sense and antisense primer sequences were 5'-GATCCCCGGCCACTCCTGCATCTTTATTCAAGA-GATAAAGATGCAGGAGTGGCCTTTTTGGAAA-3' and 5'-AGCTTTTCCAAAAAGGCCA CTCCTGCATCTTTATCTC TTGAATAAAGATGCAGGAGTGGCCGGG-3'.…”

Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment

“…Granulins and progranulin have been implicated as potent immunomodulators and cell‐cycle regulators. In the CNS, progranulin expression increases with age in both neurons and microglia, and plays a role in neurite outgrowth, synapse modification, and the prevention of neuronal apoptosis 1, 2, 3, 4. This neuroprotective function is highlighted by the relationship between progranulin and neurodegenerative disease; heterozygous loss‐of‐function mutations in the gene encoding progranulin ( GRN ) cause frontotemporal dementia (FTD),5, 6 and a common rs5848 allele in the 3′UTR of GRN has been associated with both decreased serum and brain progranulin expression levels and increased risk of developing Alzheimer's disease (AD) 7, 8, 9.…”