Progranulin expression in the developing and adult murine brain

Petkau, Terri L.; Neal, Scott J.; Orban, Paul C.; MacDonald, Jessica L.; Hill, Austin; Lu, Ge; Feldman, Howard; Mackenzie, Ian R.; Leavitt, Blair R.

doi:10.1002/cne.22430

Cited by 128 publications

(116 citation statements)

References 53 publications

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“…PGRN can be processed to granulin (GRN) peptides (4), which may have different functions (5). PGRN is expressed widely in tissues and circulates in the blood and cerebrospinal fluid (6,7).…”

Section: Introductionmentioning

confidence: 99%

Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury

et al. 2012

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Progranulin (PGRN) is a widely expressed secreted protein that is linked to inflammation. In humans, PGRN haploinsufficiency is a major inherited cause of frontotemporal dementia (FTD), but how PGRN deficiency causes neurodegeneration is unknown. Here we show that loss of PGRN results in increased neuron loss in response to injury in the CNS. When exposed acutely to 1-methyl-4-(2′-methylphenyl)-1,2,3,6-tetrahydrophine (MPTP), mice lacking PGRN (Grn -/-) showed more neuron loss and increased microgliosis compared with wild-type mice. The exacerbated neuron loss was due not to selective vulnerability of Grn -/-neurons to MPTP, but rather to an increased microglial inflammatory response. Consistent with this, conditional mutants lacking PGRN in microglia exhibited MPTP-induced phenotypes similar to Grn -/-mice. Selective depletion of PGRN from microglia in mixed cortical cultures resulted in increased death of wild-type neurons in the absence of injury. Furthermore, Grn -/-microglia treated with LPS/IFN-γ exhibited an amplified inflammatory response, and conditioned media from these microglia promoted death of cultured neurons. Our results indicate that PGRN deficiency leads to dysregulated microglial activation and thereby contributes to increased neuron loss with injury. These findings suggest that PGRN deficiency may cause increased neuron loss in other forms of CNS injury accompanied by neuroinflammation.

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Section: Introductionmentioning

confidence: 99%

Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury

et al. 2012

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“…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). …”

Section: Discussionmentioning

confidence: 99%

“…In the adult brain, PGRN is expressed in microglia, in pyramidal neurons of the cortex and hippocampus, as well as in cerebellar Purkinje cells and spinal motor neurons (Petkau et al, 2010). PGRN has been shown to play a role in promoting neuronal survival, enhancing neurite outgrowth and regulating inflammation in the central nervous system (CNS) (Guo et al, 2010;Ryan et al, 2009;Tang et al, 2011;Van Damme et al, 2008;Xu et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Activity-dependent secretion of progranulin from synapses

Petoukhov¹,

Fernando²,

Mills³

et al. 2013

Journal of Cell Science

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SummaryThe secreted growth factor progranulin (PGRN) has been shown to be important for regulating neuronal survival and outgrowth, as well as synapse formation and function. Mutations in the PGRN gene that result in PGRN haploinsufficiency have been identified as a major cause of frontotemporal dementia (FTD). Here we demonstrate that PGRN is colocalized with dense-core vesicle markers and is cotransported with brain-derived neurotrophic factor (BDNF) within axons and dendrites of cultured hippocampal neurons in both anterograde and retrograde directions. We also show that PGRN is secreted in an activity-dependent manner from synaptic and extrasynaptic sites, and that the temporal profiles of secretion are distinct in axons and dendrites. Neuronal activity is also shown to increase the recruitment of PGRN to synapses and to enhance the density of PGRN clusters along axons. Finally, treatment of neurons with recombinant PGRN is shown to increase synapse density, while decreasing the size of the presynaptic compartment and specifically the number of synaptic vesicles per synapse. Together, this indicates that activity-dependent secretion of PGRN can regulate synapse number and structure.

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“…Progranulin (PGRN) is a multifunctional secreted growth factor that is widely expressed in the developing brain but becomes progressively restricted to defined neuronal populations, including cortical and hippocampal pyramidal neurons and Purkinje cells (Daniel et al, 2000(Daniel et al, , 2003Petkau et al, 2010). Thus far, PGRN has been implicated in the regulation of neuronal survival (Van Damme et al, 2008;Ryan et al, 2009;Kleinberger et al, 2010), and treatment of neurons with exogenous PGRN has been shown to enhance neurite outgrowth (Van Damme et al, 2008;Gao et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Progranulin Deficiency Decreases Gross Neural Connectivity But Enhances Transmission at Individual Synapses

Tapia¹,

Milnerwood²,

Guo³

et al. 2011

J. Neurosci.

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Frontotemporal dementia (FTD) has been linked to mutations in the progranulin gene (GRN) that lead to progranulin (PGRN) haploinsufficiency. Thus far, our understanding of the effects of PGRN depletion in the brain has been derived from investigation of gross pathology, and more detailed analyses of cellular function have been lacking. We report that knocking down PGRN levels in rat primary hippocampal cultures reduces neural connectivity by decreasing neuronal arborization and length as well as synapse density. Despite this, the number of synaptic vesicles per synapse and the frequency of mEPSCs are increased in PGRN knockdown cells, suggesting an increase in the probability of release at remaining synapses. Interestingly, we demonstrate that the number of vesicles per synapse is also increased in postmortem brain sections from FTD patients with PGRN haploinsufficiency, relative to controls. Our observations show that PGRN knockdown severely alters neuronal connectivity in vitro and that the synaptic vesicle phenotype observed in culture is consistent with that observed in the hippocampus of FTD patients.

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Progranulin expression in the developing and adult murine brain

Cited by 128 publications

References 53 publications

Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury

Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury

Activity-dependent secretion of progranulin from synapses

Progranulin Deficiency Decreases Gross Neural Connectivity But Enhances Transmission at Individual Synapses

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