ANALYZING MICROGLIA-DERIVED TOXICITY TO MOTOR NEURONS IN ALS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Amyotrophic Lateral Sclerosis (ALS) is a late onset neurodegenerative disease leading to paralysis. Mutations in the gene for the ubiquitously expressed Cu/Zn superoxide dismutase (SOD1) are the best-known cause for familial ALS and transgenic mice constitutively expressing mutant SOD1 develop a late-onset, ALS-like disease. It is known that degeneration of upper and lower motor neurons is responsible for paralysis in ALS and that glial cell types expressing mutant SOD1 contribute to disease mechanism. We showed that microglial cells, the immune cells of the CNS, were important players, since diminishing mutant SOD1 specifically in macrophages/ microglial cells extended survival in ALS mice. Microglial cells are activated in any injury of the CNS including sporadic and familial ALS and when activated, they release factors that can be toxic or trophic for neurons. Therefore, identifying those factors could be a key to finding new targets implicated in motor neuron death. As downregulating mutant SOD1 from macrophages/microglial cells slowed disease progression in ALS mice, mutant SOD1 must act directly within microglial cells to generate toxicity toward motor neurons. Therefore, microglial cells expressing mutant or wild-type SOD1 will be screened for the different factors that they can release using Mass Spectrometry. Conditioned medium from cultured microglial cells will be used as a source of released microglial factors and medium from cells expressing mutant SOD1 will be compared to medium from wild-type SOD1 expressing microglial cells. Identification of the differences between mutant SOD1 expressing microglial cells and control microglial cells should help elucidate the intracellular pathways involved and the toxic factors released by microglial cells that contribute to motor neuron death.