THE GOLGI-APPARATUS OF SPINAL-CORD MOTOR-NEURONS IN TRANSGENIC MICE EXPRESSING MUTANT CU,ZN SUPEROXIDE-DISMUTASE BECOMES FRAGMENTED IN EARLY, PRECLINICAL STAGES OF THE DISEASE

Dominant mutations of the SOD1 gene encoding Cu,Zn superoxide dismutas e have been found in members of certain families with familial amyotro phic lateral sclerosis (ALS). To better understand the contribution of SOD1 mutations in the pathogenesis of familial ALS, we developed tran sgenic mice expressing one of the mutations found in familial ALS. The se animals display clinical and pathological features closely resembli ng human ALS. Early changes observed in these animals were intra-axona l and dendritic vacuoles due to dilatation of the endoplasmic reticulu m and vacuolar degeneration of mitochondria. We have reported that the Golgi apparatus of spinal cord motor neurons in patients with sporadi c ALS is fragmented and atrophic. In this study we show that spinal co rd motor neurons of transgenic mice for an SOD1 mutation display a les ion of the Golgi apparatus identical to that found in humans with spor adic ALS. In these mice, the stacks of the cisternae of the fragmented Golgi apparatus are shorter than in the normal organelle, and there i s a reduction in Golgi-associated vesicles and adjacent cisternae of t he rough endoplasmic reticulum. Furthermore, the fragmentation of the Golgi apparatus occurs in an early, presymptomatic stage and usually p recedes the development of the vacuolar changes. Transgenic mice overe xpressing the wild-type human superoxide dismutase are normal. In fami lial ALS, an early lesion of the Golgi apparatus of motor neurons may have adverse functional effects, because newly synthesized proteins de stined for fast axoplasmic transport pass through the Golgi apparatus.