A mouse model of familial amyotrophic lateral sclerosis expressing a mutant superoxide dismutase 1 shows evidence of disordered transport in the vasopressin hypothalamo-neurohypophysial axis

Amyotrophic lateral sclerosis (ALS) is a fatal, paralytic disorder that pri marily affects motoneurons. By combining physiological and morphological ap proaches, we examined the effect of a murine superoxide dismutase 1 (SOD1) mutation (G86R), which induces neurological disorders resembling human fami lial ALS (FALS), on the arginine vasopressin (AVP) hypothalamo-neurohypophy sial axis, an unmyelinated tract poor in neurofilaments. First, we observed that G86R mice progressively consumed more water than wild-type littermate s. Furthermore, levels of plasma AVP and neurohypophysial AVP content were decreased in the SOD1 mutant mice, whereas the amount of hypothalamic AVP i ncreased in an age-dependent manner. However, hypothalamic AVP mRNA levels were not significantly modified in these animals. At the ultrastructural le vel, we found that the neurohypophysis of G86R mice had a decreased number of neurosecretory axons. Conversely, the presence of large axon swellings w as more pronounced in the SOD1 mutant mice. In addition, the size of neuros ecretory granules was higher in G86R than in wild-type animals. All these f indings strongly suggest that the FALS-associated SOD1 mutation injures the hypothalamo-neurohypophysial axis by provoking early, progressive disturba nces in the axonal transport of neurosecretory products from neuronal perik arya to nerve terminals. This blockade could ultimately result in degenerat ion of the tract, as proposed for the myelinated, neurofilament-enriched mo tor axons affected by ALS.