[The role of extracellular α-synuclein in molecular mechanisms of cell death].

Recently published data demonstrated that increased release, oligomerization and toxicity of α-synuclein (ASN) is a key molecular process in pathophysiology of neurodegenerative diseases classified as synucleinopathies (e.g. Parkinson disease or Alzheimer's disease).

Alpha-synuclein induced cell death in mouse hippocampal (HT22) cells is mediated by nitric oxide-dependent activation of caspase-3.

Our previous studies indicated that exogenous alpha-synuclein (ASN) activates neuronal nitric oxide (NO) synthase (nNOS) in rat brain slices. The present study, carried out on immortalized hippocampal neuronal cells (HT22), was designed to extend the previous results by showing the molecular pathway of NO-mediated cell death induced by exogenous ASN. Extracellular ASN (10 microM) was found to stimulate nitric oxide synthase (NOS) and increase caspase-3 activity in HT22 cells, leading to poly(ADP-ribose) polymerase (PARP-1) cleavage.

Poly(ADP-ribose) metabolism in brain and its role in ischemia pathology.

The biological roles of poly(ADP-ribose) polymers (PAR) and poly(ADP-ribosyl)ation of proteins in the central nervous system are diverse. The homeostasis of PAR orchestrated by poly(ADP-ribose) polymerase-1 (PARP-1) and poly(ADP-ribose) glycohydrolase (PARG) is crucial for cell physiology and pathology. Both enzymes are ubiquitously distributed in neurons and glia; however, they are segregated at the subcellular level.