Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neuromuscular disease; approximately 10% of ALS patients have a family history of the disease. 20-25% of these familial ALS cases are caused by mutations in the Cu2+/Zn2+ superoxide dismutase gene (mSOD1). Overexpression of mSOD1 in transgenic mice also induces disease when ubiquitously expressed. However, evidence indicates that other cells, in addition to motor neurons, may be required to produce an ALS phenotype, i.e. non-cell autonomous. First, expression of mSOD1 in neurons-only and in astroglia-only did not produce disease; however, the level and timing of mSOD1 expression were not the same as the original mSOD1G93A mouse. Second, data from chimeric mice suggest that mSOD1-expressing neurons surrounded by normal glia appear uninjured, whereas normal neurons surrounded by mSOD-expressing glia appear abnormal. Third, pathology is present in several different cell types in the CNS, including neurons, astrocytes, and microglia. To determine the effects of mSOD1 expression in microglia and immune cells in ALS, we chose to use the PU.1-/- mouse. At birth, these mice lack macrophages, neutrophils, T and B cells, and importantly microglia; such mice survive only after bone marrow transplantation, resulting in donor-derived CNS microglia. Specifically, our aims are:
Specific Aim 1 : To determine if mSOD1 expression in microglia and immune cells alone can induce an ALS-like disease and/or initiate subclinical pathology. We are transplanting PU.1 -/- mice with mSOD1-, normal human (h)SOD1, and wildtype-derived bone marrow. PU.1 -/- mice transplanted with mSOD1 bone marrow did not appear to show any overt signs of motoneuron disease; even though the transplanted microglia may be morphologically different than microglia in control mice. We will examine these mice for subclinical pathology.
Specific Aim 2 : To determine if mSOD1 expression in microglia and immune cells is required for the initiation and/or amplification of an ALS-like disease in the mSOD1 mouse. We are transplanting the mSOD1 mice crossed with the PU.1 -/- mice (mSOD1/PU.I-/-). mSOD1/PU.1 -/- mice transplanted with wildtype bone marrow exhibit an ALS-like phenotype. Interestingly, the disease duration with these few mice may be longer than the duration of the mSOD1/PU.1 -/- mice transplanted with mSOD1 bone marrow.
Specific Aim 3 : To define potential mechanisms of microglia-mediated motor neuron injury. We are culturing primary motor neurons, which are injured by activated wildtype microglia, mSOD1 primary microglia appear more activated and we will assess their ability to injure wildtype and mSOD1 motor neurons.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CNBT (01))
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Refolo, Lorenzo
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Methodist Hospital Research Institute
United States
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