Progressive loss of striatal neurons causes motor dysfunction in MND2 mutant mice and is not prevented by Bcl-2

The mouse mutant "motoneuron disease 2" (MND2, mnd2 on Chr 6) was originally characterized as a spinal muscular atrophy (SMA) because degenerating motoneurons were observed in late stages of the disease. MND2 mutants exhibit a progressive phenotype with neurological symptoms that begin at postnatal day (dP) 20 and include involuntary movements, abnormal postures, akinesis, and death between dP 30 and 40. Unexpectedly, there was no induction of acetylcholine receptor alpha subunit mRNA in skeletal muscle of MND2 mice, an indicator of muscle denervation due to motoneuron loss. Rather, we found a massive loss of striatal neurons beginning at dP 25. Histochemical and ultrastructural analysis revealed nuclear pyknosis, chromatin condensation, and organelle disintegration, combined features of apoptosis and necrosis, characteristic for excitotoxic cell death. Striatal neurodegeneration was accompanied by a pronounced astrogliosis and activation of microglia with macrophage morphology. Motor abnormalities and neuronal loss in MND2 mice were not prevented by neuronal overexpression of a Bcl-2 transgene. Transcripts of several cytokines, including Interleukin-1beta and tumor necrosis factor alpha, were upregulated in the CNS, as well as in lung and spleen, indicating that the mnd2 mutation causes additional pathological effects outside the CNS. Since a 50% reduction in the number of striatal neurons is sufficient to account for the neurological phenotype of MND2 mice, MND2 may be classified as striatal atrophy rather than a primary motor neuron disease. Thus, MND2 mutant mice may provide useful insights into molecular events underlying striatal cell death.