Neuroserpin: structure, function, physiology and pathology

Cell Mol Life Sci. 2021 Oct;78(19-20):6409-6430. doi: 10.1007/s00018-021-03907-6. Epub 2021 Aug 17.


Neuroserpin is a serine protease inhibitor identified in a search for proteins implicated in neuronal axon growth and synapse formation. Since its discovery over 30 years ago, it has been the focus of active research. Many efforts have concentrated in elucidating its neuroprotective role in brain ischemic lesions, the structural bases of neuroserpin conformational change and the effects of neuroserpin polymers that underlie the neurodegenerative disease FENIB (familial encephalopathy with neuroserpin inclusion bodies), but the investigation of the physiological roles of neuroserpin has increased over the last years. In this review, we present an updated and critical revision of the current literature dealing with neuroserpin, covering all aspects of research including the expression and physiological roles of neuroserpin, both inside and outside the nervous system; its inhibitory and non-inhibitory mechanisms of action; the molecular structure of the monomeric and polymeric conformations of neuroserpin, including a detailed description of the polymerisation mechanism; and the involvement of neuroserpin in human disease, with particular emphasis on FENIB. Finally, we briefly discuss the identification by genome-wide screening of novel neuroserpin variants and their possible pathogenicity.

Keywords: Epilepsy; Neurodegenerative disease; Pathogenic variants; Serpins; Synaptic plasticity; Tissue-type plasminogen activator.

Publication types

  • Review

MeSH terms

  • Animals
  • Axons / metabolism
  • Epilepsies, Myoclonic / metabolism
  • Heredodegenerative Disorders, Nervous System / metabolism
  • Humans
  • Neurodegenerative Diseases / metabolism
  • Neurons / metabolism
  • Neuropeptides / metabolism*
  • Neuroserpin
  • Polymerization
  • Serpins / metabolism*


  • Neuropeptides
  • Serpins

Supplementary concepts

  • Familial encephalopathy with neuroserpin inclusion bodies