Activity-dependent secretion of progranulin from synapses

Abstract

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.

Progranulin levels in status epilepticus as a marker of neuronal recovery and neuroprotection

“…Progranulin plays an important role in neuroprotective and neuroinflammatory mechanisms [3,11]. In our cohort, CSF PRGN levels were not significantly elevated following a SE compared to the CSF PRGN levels following a single tonic-clonic seizure.…”

“…Therefore, the positive correlation between histopathological findings and CSF PRGN is well known. Also, the neuronal PRGN has an impact on synapse regulation and is modulated by neuronal activity [11]. Considering these results, an elevated CSF PRGN could have been possible.…”

BDNF Serum Levels with Respect to Multidimensional Assessment in Amyotrophic Lateral Sclerosis

“…Furthermore, BDNF appears to possess neurotrophic function on motor system-related neurons, promoting cell survival in the cerebellum, basal ganglia, and spinal cord [42]. Interestingly, peripheral BDNF is stored in platelets that actively take it up from the bloodstream and release it upon activation [40], and it is cotransported with another growth factor, progranulin, in which haploinsufficiency has been identified as a major cause of frontotemporal dementia [43] and which is a possible modifier of ALS course [44]. …”

Progranulin Gene Delivery Protects Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease

“…Overall, however, ND-602 treatment more than doubled measures of PGRN immonolabeling in the SNc over sham controls. As PGRN is a secreted factor [24], that acts extracellularly to activate cell survival signalling, it may be that not all nigral neurons are required to be transfected in order to be protected.…”