New mechanism for dementia?

Hyperactive immune cells that engulf dying and injured cells before they have a chance to recover may contribute to neurodegeneration characteristic of some diseases, posing a previously unreported mechanism for dementia, a linkurl:paper;http://www.pnas.org/content/early/2011/02/23/1100650108.abstract from the __Proceedings of the National Academy of Sciences__ reports today (February 28).

Human brain with frontal lobe degeneration
Image: WikiCommons/Talgraf777

"This is a very exciting and credible piece of work," said linkurl:John Hardy,;http://www.ucl.ac.uk/neuroscience/Page.php?ID=12&ResearcherID=173 a neuroscientist at University College London who was not involved in the study. "This paper offers a credible link to the precise mechanism of [certain kinds neurodegenerative] disease."Most neurodegenerative diseases are thought to be caused by the toxic accumulation of insoluble protein aggregates in the brain, which is toxic to cells. Additionally, defects in the pathway regulating apoptosis (programmed cell death) have been proposed as a mechanism of neurodegeneration. Defects in mitochondria, for example, have been shown to increase apoptosis in neurons, resulting in neurodegeneration.Examining Caenorhabditis elegans, biochemist linkurl:Cynthia Kenyon;http://kenyonlab.ucsf.edu/html/ck_biosketch.html of the University of California, San Francisco and her colleagues found preliminary evidence for a different pathway of neurodegeneration -- one that involves the clearance of apoptotic cells by overly active phagocytic immune cells, such as macrophages, leading to widespread cell loss over time. Spurring the unhealthy appetite of these macrophages, the study suggests, are mutations in the gene that codes for progranulin -- a glycoprotein secreted by neurons and microglia (among and other cell types) that is known to play a role in embryogenesis, inflammation, and wound healing. Such mutations were recently found to cause neurodegeneration in people with frontotemporal lobar degeneration, a family of progressive neurodegenerative diseases with adverse effects in behavior and cognition, but progranulin's role in the disease has remained a mystery.The new study provides the first hint at this mechanism. In the worms, Kenyon and her team observed that, compared to their control counterparts, progranulin-deficient worms showed fewer cells in the throes of apoptosis throughout their lifespan. At first glance, the detection of fewer dying cells in the mutant worms caught the researchers by surprise -- neurodegenerative diseases are characterized by widespread cell loss, so they had expected to find more dying cells in these individuals. But a closer look revealed that the difference stemmed not from the number of cells undergoing apoptosis, but the rate at which they were being removed by phagocytic cells. The apoptotic cells "weren't around long enough to be counted," Kenyon explained.Although a direct link to neurodegeneration is yet to be determined, Kenyon said, this observation could point to an entirely new mechanism for neuron loss. "If you have a mutation that makes engulfing cells more rabid," she explained, "then maybe during the normal course of life, a cell that is slightly damaged that would have recovered would now instead be cleared."A.W. Kao et al., "A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells," PNAS doi:10.1073/pnas.1100650108, 2011
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[28th February 2011]