Role of sphingolipid-mediated cell death in neurodegenerative diseases

Toshio Ariga, W. David Jarvis, Robert K. Yu

Research output: Contribution to journalReview articlepeer-review

172 Scopus citations

Abstract

The metazoan nervous system gives rise intradevelopmentally to many more 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 army of 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 peripheral nervous system (CNS and PNS) structures. Although the initiation of neuronal apoptosis in response to numerous extracellular agents has been widely reported, the regulatory mechanisms underlying this mode of cell death remain incompletely understood. In recent years, the contribution of lipid-dependent signaling systems, such as the sphingomyelin pathway, to regulation of cell survival has received considerable attention, leading to the identification of lethal fractions for the lipid effectors ceramide and sphingosine in both normal and pathophysiological conditions. Moreover, the apoptotic capacities of several cytotoxic receptor systems (e.g., CD120a, CD95) and many environmental stresses (e.g., ionizing radiation, heat-shock, oxidative stress) are now known to derive from the activation of multiple signaling cascades by ceramide or, under some circumstances, by sphingosine. Inappropriate initiation of apoptosis has been proposed to underlie the progressive neuronal attrition associated with various neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and other neurological disorders that are characterized by the gradual loss of specific populations of neurons. 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 Guillain-Barre syndrome, demyelinating polyneuropathy, and motoneuron disease, persistent immunological attack of microvascular endothelial cells by glycolipid- directed autoantibodies may lead to extensive cellular damages, resulting in increased permeability across brain-nerve barrier (BNB) and/or blood-brain barrier (BBB).

Original languageEnglish (US)
Pages (from-to)1-16
Number of pages16
JournalJournal of Lipid Research
Volume39
Issue number1
StatePublished - Jan 1998
Externally publishedYes

Keywords

  • Alzheimer disease
  • Apoptosis
  • Ceramide
  • Gangliosides
  • Glycolipids
  • Lysosphingolipids
  • Neurodegenerative disease
  • Programmed cell death
  • Sphingoli pids
  • Sphingomyelin
  • Sphingosine

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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