Microglial Upregulation of Progranulin as a Marker of Motor Neuron Degeneration

Abstract

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are overlapping neurodegenerative disorders. Mutations in the growth factor progranulin (PGRN) gene cause FTLD, sometimes in conjunction with ALS; such mutations are also observed in some ALS patients. Most PGRN mutations underlying FTLD are null mutations that result in reduced PGRN levels. We investigated PGRN expression in human ALS and in mouse models of motor neuron degeneration. Progranulin plasma or CSF levels in newly diagnosed ALS patients did not differ from those in healthy or disease controls (PGRN mutation-negative FTLD and Alzheimer disease patients). In the mutant SOD1 mouse model of ALS, spinal cord PGRN levels were normal in presymptomatic animals but increased during the degenerative process. This increase in PGRN correlated with enhanced expression of PGRN in microglia. In CSF, PGRN levels were normal in presymptomatic and early symptomatic animals, but with disease progression, a raise in PGRN was detectable. These data indicate that upregulation of PGRN is a marker of the microglial response that occurs with progression in motor neuron diseases.

Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in <b><i>GRN</i></b>-Negative Frontotemporal Dementia

“…Compared to our GRN -negative FTD cohort, the progranulin level was significantly reduced in her CSF (t 33 = 7.80, p < 0.001), but not in her serum (t 33 = -0.90, p = 0.373, 2-sided 1-sample t test). Indeed, her decreased CSF level of progranulin was comparable to the decreased CSF levels observed in our patients with GRN LoF mutations (and those in other studies) [4,25], thus supporting a pathogenic effect of this novel GRN missense mutation.…”

“…Our findings show that the CSF levels of progranulin are reduced, even in mutation-negative FTD, and that this reduction extends beyond the recognised modification of CSF progranulin levels by the SNP rs5848 [24]. This suggests that decreased central nervous progranulin levels not only contribute to FTD in the relatively rare cases of pathogenic GRN mutations [4,25], but could actually represent a more general mechanism in FTD neurodegeneration. Specifically, a shortage of CNS progranulin might lead to insufficient trophic support for the cerebral neurons in FTD in general, not just in GRN- positive FTD [5,28].…”

CSF markers in amyotrophic lateral sclerosis

“…In the newly diagnosed ALS progranulin CSF or plasma levels did not differ from healthy or disease controls, but with a disease progression their increase was seen. The upregulation of PGRN, which can protect neurons from degeneration, is a marker of the microglial response according to CNS injury and may be important in microglial proliferation (Philips et al 2010). …”

Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis

“…Potentially, mSOD1 released by motor neurons activate astrocytes and microglia via a TLR response [122,123]. Intriguingly, mSOD1 has been demonstrated to transform and activate microglia to a M1 proinflammatory state, but mSOD1 also can induce a neuroprotective state with production of IGF-1 and progranulin secretion in certain conditions [53,122,[124][125][126][127]. Both of these states can exist during the course of ALS and are determined by the cytokine milieu created in response to motor neuron injury.…”