Astrocytic proliferation and hypertrophy (astrogliosis) are associated with neuronal injury. However, neither the temporal nor the spatial relationship between astrocytes and injured neurons is clear, especially in neurodegenerative diseases. We investigated these questions in a mouse amyotrophic lateral sclerosis (ALS) model. The initial increase in astrogliosis coincided with the onset of clinical disease and massive mitochondrial vacuolation in motor neurons. After disease onset, astrogliosis increased further in parallel with the number of degenerating motor neurons. Examination of individual astrocytes by three-dimensional reconstruction revealed that astrocytes extended their processes toward, wrapped around, and sometimes penetrated vacuoles derived from neuronal mitochondria. These results show a close temporal correlation between the onset of neuronal degeneration and the beginning of astrogliosis in this neurodegenerative disease and reveal a novel spatial relationship that is consistent with the view that astrocytes play an active role in the neuronal degeneration process.

Amyotrophic lateral sclerosis (ALS) involves motor neuron degeneration, skeletal muscle atrophy, paralysis, and death. Mutations in Cu,Zn superoxide dismutase (SOD1) are one cause of the disease. Mice transgenic for mutated SOD1 develop symptoms and pathology similar to those in human ALS. To understand the disease mechanism, we developed a simple behavioral assay for disease progression in mice. Using this assay, we defined four stages of the disease in mice expressing G93A mutant SOD1. By studying mice with defined disease stages, we tied several pathological features into a coherent sequence of events leading to motor neuron death. We show that onset of the disease involves a sharp decline of muscle strength and a transient explosive increase in vacuoles derived from degenerating mitochondria, but little motor neuron death. Most motor neurons do not die until the terminal stage, approximately 9 weeks after disease onset. These results indicate that mutant SOD1 toxicity is mediated by damage to mitochondria in motor neurons, and this damage triggers the functional decline of motor neurons and the clinical onset of ALS. The absence of massive motor neuron death at the early stages of the disease indicates that the majority of motor neurons could be rescued after clinical diagnosis.