Dysfunction of constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis: Implication for protein aggregation and immune response

Caterina Bendotti, Marianna Marino, Cristina Cheroni, Elena Fontana, Valeria Crippa, Angelo Poletti, Silvia De Biasi

Research output: Contribution to journalArticlepeer-review

Abstract

The ubiquitin-proteasome system (UPS) is the major intracellular proteolytic mechanism controlling the degradation of misfolded/abnormal proteins. A common hallmark in amyotrophic lateral sclerosis (ALS) and in other neurodegenerative disorders is the accumulation of misfolded/abnormal proteins into the damaged neurons, leading to the formation of cellular inclusions that are mostly ubiquitin-positive. Although proteolysis is a complex mechanism requiring the participation of different pathways, the abundant accumulation of ubiquitinated proteins strongly suggests an important contribution of UPS to these neuropathological features. The use of cellular and animal models of ALS, particularly those expressing mutant SOD1, the gene mutation most represented in familiar ALS, has provided significant evidence for a role of UPS in protein inclusions formation and motor neuron death. This review will specifically discuss this piece of evidence and provide suggestions of potential strategies for therapeutic intervention. We will also discuss the finding that, unlike the constitutive proteasome subunits, the inducible subunits are overexpressed early during disease progression in SOD1 mice models of ALS. These subunits form the immunoproteasome and generate peptides for the major histocompatibility complex class I molecules, suggesting a role of this system in the immune responses associated with the pathological features of ALS. Since recent discoveries indicate that innate and adaptive immunity may influence the disease process, in this review we will also provide evidence of a possible connection between immune-inflammatory reactions and UPS function, in the attempt to better understand the etiopathology of ALS and to identify appropriate targets for novel treatment strategies of this devastating disease.

Original languageEnglish
Pages (from-to)101-126
Number of pages26
JournalProgress in Neurobiology
Volume97
Issue number2
DOIs
Publication statusPublished - May 2012

Keywords

  • Astrocyte
  • Immune system
  • Microglia
  • Motor neuron
  • Neurodegeneration
  • NSC34 cells
  • Oxidative stress
  • Spinal cord
  • Superoxide dismutase
  • T lymphocytes
  • Transgenic mice

ASJC Scopus subject areas

  • Neuroscience(all)

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