Protein Disulphide Isomerases: emerging roles of PDI and ERp57 in the nervous system and as therapeutic targets for ALS

Research output: Contribution to journalReview articleResearchpeer-review

Abstract

Introduction: There is increasing evidence that endoplasmic reticulum (ER) chaperones Protein Disulphide Isomerase (PDI) and ERp57 (endoplasmic reticulum protein 57) are protective against neurodegenerative diseases related to protein misfolding, including Amyotrophic Lateral Sclerosis (ALS). PDI and ERp57 also possess disulphide interchange activity, in which protein disulphide bonds are oxidized, reduced and isomerized, to form their native conformation. Recently, missense and intronic variants of PDI and ERp57 were associated with ALS, implying that PDI proteins are relevant to ALS pathology. Areas covered: Here, we discuss possible implications of the PDI and ERp57 variants, as well as recent studies describing previously unrecognized roles for PDI and ERp57 in the nervous system. Therapeutics based on PDI may therefore be attractive candidates for ALS. However, in addition to its protective functions, aberrant, toxic roles for PDI have recently been described. These functions need to be fully characterized before effective therapeutic strategies can be designed. Expert opinion: These disease-associated variants of PDI and ERp57 provide additional evidence for an important role for PDI proteins in ALS. However, there are many questions remaining unanswered that need to be addressed before the potential of the PDI family in relation to ALS can be fully realized.

LanguageEnglish
Pages37-49
Number of pages13
JournalExpert Opinion on Therapeutic Targets
Volume21
Issue number1
DOIs
Publication statusPublished - 2 Jan 2017

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Protein Disulfide-Isomerases
Amyotrophic Lateral Sclerosis
Neurology
Endoplasmic Reticulum
Nervous System
Proteins
Therapeutics
Disulfides
Neurodegenerative diseases
Poisons
Expert Testimony
Interchanges
Pathology
Neurodegenerative Diseases
Conformations

Keywords

  • Amyotrophic Lateral Sclerosis (ALS)
  • ER chaperones
  • ERp57 (endoplasmic reticulum protein 57)
  • nervous system
  • neurodegeneration
  • PDIA1
  • PDIA3
  • Protein Disulphide Isomerase (PDI)
  • therapeutics
  • variants

Cite this

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title = "Protein Disulphide Isomerases: emerging roles of PDI and ERp57 in the nervous system and as therapeutic targets for ALS",
abstract = "Introduction: There is increasing evidence that endoplasmic reticulum (ER) chaperones Protein Disulphide Isomerase (PDI) and ERp57 (endoplasmic reticulum protein 57) are protective against neurodegenerative diseases related to protein misfolding, including Amyotrophic Lateral Sclerosis (ALS). PDI and ERp57 also possess disulphide interchange activity, in which protein disulphide bonds are oxidized, reduced and isomerized, to form their native conformation. Recently, missense and intronic variants of PDI and ERp57 were associated with ALS, implying that PDI proteins are relevant to ALS pathology. Areas covered: Here, we discuss possible implications of the PDI and ERp57 variants, as well as recent studies describing previously unrecognized roles for PDI and ERp57 in the nervous system. Therapeutics based on PDI may therefore be attractive candidates for ALS. However, in addition to its protective functions, aberrant, toxic roles for PDI have recently been described. These functions need to be fully characterized before effective therapeutic strategies can be designed. Expert opinion: These disease-associated variants of PDI and ERp57 provide additional evidence for an important role for PDI proteins in ALS. However, there are many questions remaining unanswered that need to be addressed before the potential of the PDI family in relation to ALS can be fully realized.",
keywords = "Amyotrophic Lateral Sclerosis (ALS), ER chaperones, ERp57 (endoplasmic reticulum protein 57), nervous system, neurodegeneration, PDIA1, PDIA3, Protein Disulphide Isomerase (PDI), therapeutics, variants",
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Protein Disulphide Isomerases : emerging roles of PDI and ERp57 in the nervous system and as therapeutic targets for ALS. / Perri, Emma; Parakh, Sonam; Atkin, Julie.

In: Expert Opinion on Therapeutic Targets, Vol. 21, No. 1, 02.01.2017, p. 37-49.

Research output: Contribution to journalReview articleResearchpeer-review

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AB - Introduction: There is increasing evidence that endoplasmic reticulum (ER) chaperones Protein Disulphide Isomerase (PDI) and ERp57 (endoplasmic reticulum protein 57) are protective against neurodegenerative diseases related to protein misfolding, including Amyotrophic Lateral Sclerosis (ALS). PDI and ERp57 also possess disulphide interchange activity, in which protein disulphide bonds are oxidized, reduced and isomerized, to form their native conformation. Recently, missense and intronic variants of PDI and ERp57 were associated with ALS, implying that PDI proteins are relevant to ALS pathology. Areas covered: Here, we discuss possible implications of the PDI and ERp57 variants, as well as recent studies describing previously unrecognized roles for PDI and ERp57 in the nervous system. Therapeutics based on PDI may therefore be attractive candidates for ALS. However, in addition to its protective functions, aberrant, toxic roles for PDI have recently been described. These functions need to be fully characterized before effective therapeutic strategies can be designed. Expert opinion: These disease-associated variants of PDI and ERp57 provide additional evidence for an important role for PDI proteins in ALS. However, there are many questions remaining unanswered that need to be addressed before the potential of the PDI family in relation to ALS can be fully realized.

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