ROLE OF SPHINGOLIPID-MEDIATED CELL-DEATH IN NEURODEGENERATIVE DISEASES

The metazoan nervous system gives rise intradevelopmentally to many mo re neurons than ultimately survive in the adult. Such excess cells are eliminated through programmed cell death or apoptosis. As is true for cells of other lineages, neuronal survival is sustained by an array o f growth factors, such that withdrawal of neurotrophic support results in apoptotic cell death. Apoptosis is therefore believed to represent a beneficial process essential to normal development of central and p eripheral nervous system (CNS and PNS) structures. Although the initia tion of neuronal apoptosis in response to numerous extracellular agent s has been widely reported, the regulatory mechanisms underlying this mode of cell death remain incompletely understood. In recent years, th e contribution of lipid-dependent signaling systems, such as the sphin gomyelin path way, to regulation of cell survival has received conside rable attention, leading to the identification of lethal functions for the lipid effecters ceramide and sphingosine in both normal and patho physiological conditions. Moreover, the apoptotic capacities of severa l cytotoxic receptor systems (e.g., CD120a, CD95) and many environment al stresses (e.g., ionizing radiation, heat-shock, oxidative stress) a re now known to derive from the activation of multiple signaling casca des by ceramide or, under some circumstances, by sphingosine. Inapprop riate initiation of apoptosis has been proposed to underlie the progre ssive neuronal attrition associated with various neurodegenerative dis eases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyo trophic lateral sclerosis (ALS), and other neurological disorders that are characterized by the gradual loss of specific populations of neur ons. In such pathophysiological states, neuronal cell death can result in specific disorders of movement and diverse impairments of CNS and PNS function. In some autoimmune neurological diseases such as Guillai n-Barre syndrome, demyelinating polyneuropathy and motoneuron disease, persistent immunological attack of microvascular endothelial cells by glycolipid-directed autoantibodies may lead to extensive cellular dam ages, resulting in increased permeability across brain-nerve barrier ( BNB) and/or blood-brain barrier (BBB).