Pathophysiological Roles of Intracellular Proteases in Neuronal Development and Neurological Diseases

  • Tatsurou YagamiEmail author
  • Yasuhiro Yamamoto
  • Hiromi Koma


Proteases are classified into six distinct classes (cysteine, serine, threonine, aspartic, glutamic, and metalloproteases) on the basis of catalytic mechanism. The cellular control of protein quality senses misfolded or damaged proteins principally by selective ubiquitin-proteasome pathway and non-selective autophagy-lysosome pathway. The two pathways do not only maintain cell homeostasis physiologically, but also mediate necrosis and apoptosis pathologically. Proteasomes are threonine proteases, whereas cathepsins are lysosomal aspartic proteases. Calpains are non-lysosomal cysteine proteases and calcium-dependent papain-like enzyme. Calpains and cathepsins are involved in the neuronal necrosis, which are accidental cell death. Necrosis is featured by the disruption of plasma membranes and lysosomes, the loss of ATP and ribosomes, the lysis of cell and nucleus, and the caspase-independent DNA fragmentation. On the other hand, caspases are cysteine endoproteases and mediate neuronal cell death such as apoptosis and pyroptosis, which are programmed cell death. In the central nervous system, necroptosis, ferroptosis and autophagic cell death are also classified into programmed cell death. Neuronal apoptosis is characterized by cell shrinkage, plasma membrane blebbing, karyorrhexis, chromatin condensation, and DNA fragmentation. Necroptosis and pyroptosis are necrotic and lytic forms of programmed cell death, respectively. Although autophagy is involved in cell survival, it fails to maintain cellular homeostasis, resulting in autophagic cell death. Ferroptosis is induced by reactive oxygen species in excitotoxicity of glutamate and ischemia-reperfusion. Apoptosis and pyroptosis are dependent on caspase-3 and caspase-1, respectively. Autophagic cell death and necroptosis are dependent on calpain and cathepsin, respectively, but independent of caspase. Although apoptosis has been defined by the absence of morphological features of necrosis, the two deaths are both parts of a continuum. The intracellular proteases do not only maintain cell homeostasis but also regulate neuronal maturation during the development of embryonic brain. Furthermore, neurodegenerative diseases are caused by the impairment of quality control mechanisms for a proper folding and function of protein.


Neuronal cell death Apoptosis Autophagy Ferroptosis Necrosis Necroptosis Oncosis Pyroptosis 



Arachidonic acid

Amyloid β


Autophagic cell death


Alzheimer’s disease


Apoptosis-inducing factor


Autophagy–lysosome pathway


Amyotrophic lateral sclerosis


Amyloid precursor protein


Apoptosis specific-like adaptor protein


Autophagy-related genes


Autophagic vacuoles


Intracellular calcium level


Caspase recruitment domain


Creutzfeldt–Jakob disease


Chaperone-mediated autophagy


Central nervous system


Chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells


Cerebral cortex




Cyclopentenone prostaglandins




Danger-associated molecular patterns


Death-inducing signaling complex


Endoplasmic reticulum


Extracellular signal-regulated kinase


Fas-associated death domain


Glutathione peroxidase-4




Huntington’s disease




c-Jun N2-terminal kinase




L-type voltage-dependent Ca2+ channels


Mitogen-activated protein kinase


Middle cerebral artery


Mammalian target of rapamycin


Mixed-lineage kinase domain-like protein


Mitochondrial permeability transition pore


Neurofibrillary tangles


Nerve growth factor


Nucleotide-binding oligomerization domain-like receptor


NADPH oxygenase


Neurotrophic receptors


Pathogen-associated molecular patterns


Poly(ADP-ribose) polymerase


Programmed cell death


Parkinson’s disease


Propidium iodide


Phosphatidylinositol 3-kinase


Peroxisome proliferator-activated receptor-γ


Cellular prion protein


Scrapie prion protein


Pattern-recognition receptors




p53 upregulated modulator of apoptosis


Reactive oxygen species


Receptor-interacting protein


Superoxide dismutase


Secreted phospholipase A2




Tumor necrosis factor α


TNF-related apoptosis-inducing ligand


Unc-51 like autophagy activating kinase1


Ubiquitin–proteasome pathway


Unfolded protein response


Ventral spinal cord


15-deoxy-Δ12,14 prostaglandin J2



The work presented in the submitted manuscript was funded by Grant-in-Aid 17K08327 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.


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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Himeji Dokkyo UniversityHimejiJapan

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