Editors' ChoiceNeurodegeneration

Glial Death Star

Science Signaling  12 Mar 2013:
Vol. 6, Issue 266, pp. ec61
DOI: 10.1126/scisignal.2004131

Communication between neurons and glia is essential for development and function of the nervous system, and dysregulation of these bidirectional pathways leads to neuropathologies. Neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), are often characterized by reactive astrocytes that are neurotoxic or show reduced neuroprotective activity, thus promoting neuron loss. To identify factors that confer neurotoxicity to reactive glia, Bi et al. surveyed factors secreted from forebrain slices from rats in which microglia and astrocytes were activated by transgenically expressing an ALS-associated allele of the TAR DNA-binding protein 43 (TDP-43) in the forebrain. In the TDP-43 model, transgenic rats developed FTLD or motor neuron degeneration similar to ALS, depending on the timing of transgene induction. After controlling for the glial reactivity that normally accompanies brain slice culture, the authors identified lipocalin 2 (lcn2) as a neurotoxic factor secreted from reactive astrocytes. Whereas conditioned medium from transgenic TDP-43 brain slice cultures induced the death of cortical neurons in slices from control rats, conditioned medium from which lcn2 had been immunodepleted did not. Synthetic lcn2 induced the death of several types of cultured neurons but did not induce the death of cultured astrocytes, microglia, or oligodendrocytes. Cortical and spinal motor neurons from two different rat neurodegeneration models were more likely to die in response to lcn2 compared with neurons from healthy rats. Lcn2 accumulated in and colocalized with an astrocytic marker in spinal cords of transgenic TDP-43 rats that showed ALS-like symptoms. Transcripts for lcn2 were increased in the brains of rats showing FTLD phenotypes due to transgenic expression of mutant TDP-43 and in two other rat models of neurodegeneration. Lcn2 was more abundant in brain tissue samples from FTLD patients compared with samples from patients without neurodegenerative disease. An increase in lcn2 abundance in cerebrospinal fluid has been previously associated with Alzheimer’s disease in humans and in rat models of neurodegeneration. This correlation in patients combined with the results from Bi et al. suggest that lcn2 plays an important role in neurodegeneration and might be useful as a therapeutic target or as a marker for the progression of neurodegenerative disease.

F. Bi, C. Huang, J. Tong, G. Qiu, B. Huang, Q. Wu, F. Li, Z. Xu, R. Bowser, X.-G. Xia, H. Zhou, Reactive astrocytes secrete lcn2 to promote neuron death. Proc. Natl. Acad. Sci. U.S.A. 110, 4069–4074 (2013). [Abstract] [Full Text]