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Keywords:

  • endoplasmic reticulum stress;
  • inclusion body;
  • neurodegerative dementia;
  • ubiquitin–proteasome system;
  • unfolded protein response

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INCLUSION BODIES IN NEURODEGERATIVE DEMENTIAS
  5. MECHANISM OF UPS PROTEOLYSIS AND NEURODEGENERATIVE DEMENTIA
  6. RELATIONSHIP BETWEEN UPS AND THE ENDOPLASMIC RETICULUM
  7. CONCLUSION
  8. REFERENCES

Recently, it was shown that inclusion bodies consisting of aberrant protein aggregation are a common pathological finding in neurodegenerative dementias. It is also believed that the ubiquitin–proteasome system (UPS) is involved in these aberrant aggregations. Because the UPS is related to the unfolded protein response (UPR) in the endoplasmic reticulum (ER) through ER-associated degradation (ERAD), we propose that the mechanism of neurodegeneration is as follows: (i) aberrant protein aggregation overloads the UPS; (ii) the disturbed UPS affects ERAD; (iii) disturbed ERAD impairs UPR; and (iv) prolonged UPR causes ER-mediated apoptosis.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INCLUSION BODIES IN NEURODEGERATIVE DEMENTIAS
  5. MECHANISM OF UPS PROTEOLYSIS AND NEURODEGENERATIVE DEMENTIA
  6. RELATIONSHIP BETWEEN UPS AND THE ENDOPLASMIC RETICULUM
  7. CONCLUSION
  8. REFERENCES

There are various causes of dementia, which has led to the classification of neurodegenerative dementias as either primary dementias, which occur as a result of damage to the central nervous system (CNS) itself, or as secondary dementias, which occur as a result of other events that do not affect the CNS. The causes of most neurodegenerative dementias remain unknown. However, these dementias all share a common feature in that they are neurodegerative disorders occurring from gradual neuronal death in various brain regions. For most neurodegerative disorders, specific inclusion bodies are observed in lesioned brains of patients, suggesting that the disorders are products of a common pathological process. Recently, it has been shown that each inclusion body consists of aberrant protein aggregation.1 Studies on the mechanisms involved in the formation of aberrant protein aggregation have become the main topic of interest of research related to neurodegerative disorders.

INCLUSION BODIES IN NEURODEGERATIVE DEMENTIAS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INCLUSION BODIES IN NEURODEGERATIVE DEMENTIAS
  5. MECHANISM OF UPS PROTEOLYSIS AND NEURODEGENERATIVE DEMENTIA
  6. RELATIONSHIP BETWEEN UPS AND THE ENDOPLASMIC RETICULUM
  7. CONCLUSION
  8. REFERENCES

Inclusion bodies are common features of neurodegenerative disorders. Alzheimer's disease (AD), a representative of degenerative dementia, is characterized by senile plaques and neurofibrillary tangles as neuropathological tissues consisting of β-amyloid proteins (Aβ) and highly phosphorylated tau proteins, respectively. In AD, the amyloid cascade hypothesis has been proposed2 and cerebral Aβ accumulation is thought to primarily affect the AD brain. Subsequent steps in the disease process include neurofibrillary tangles of tau proteins, classifying the disease as amyloidopathy.

Tauopathy refers to disorders including neurofibrillary tangles consisting of highly phosphorylated tau in neurons or glia. Frontotemporal dementia, corticobasal degeneration and progressive supranuclear palsy belong to this category.

In synucleinopathy, Lewy bodies consisting of α-synuclein are observed in neurons. Diffuse Lewy body disease and Parkinson's disease are classified in this category.

Polyglutamine diseases, such as Huntington's disease, are disorders with abnormally extended polyglutamine chains in intraneuronal inclusions due to expansion of the CAG repeat in a causal gene.

In prion diseases, some factors contain aberrant prions invading neuronal cells and convert normal prions into abnormal ones. Progressive abnormalities of prions result in accumulation of prions in neurons.

Generally, inclusion bodies seen in neurodegenerative disorders are composed of unfolded and insoluble proteins that are highly ubiquitinated. Considering this fact in neurodegerative disorders, the proteins that should have been metabolized in the ubiquitin-proteasome system (UPS) accumulate for some unknown reason to form inclusion bodies.

MECHANISM OF UPS PROTEOLYSIS AND NEURODEGENERATIVE DEMENTIA

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INCLUSION BODIES IN NEURODEGERATIVE DEMENTIAS
  5. MECHANISM OF UPS PROTEOLYSIS AND NEURODEGENERATIVE DEMENTIA
  6. RELATIONSHIP BETWEEN UPS AND THE ENDOPLASMIC RETICULUM
  7. CONCLUSION
  8. REFERENCES

Proteolysis of the UPS begins with the binding of ubiquitin to the ε-amino group of a lysine residue on a target protein with covalent bonds, in an ATP-dependent manner. The ubiquitin-activating enzyme (E1) first recruits ubiquitin and passes it to the ubiquitination enzyme (E2). Then, E2 and the target protein bind to ubiquitin ligase (E3) to allow ubiquitin to bind to the target protein. By repeating this reaction, ubiquitin is added to the target protein in sequence to form a poly ubiquitin chain. The target protein containing this poly ubiquitin chain (more than four ubiquitin molecules) is recognized by 26S proteasome and is selectively degraded. Prior to degradation in the proteasome, ubiquitins are removed from the target proteins for recycling by a de-ubiquitin enzyme and target proteins are chopped up into small peptides. Intervention of UPS was clarified by studies on familial degenerative dementia due to abnormal genes.3,4 Parkin, a causal gene of early onset autosomal recessive inheritance-related Parkinson's disease was identified as E3 itself. Metabolism of Peal receptors by the proteasome deteriorates to cause the accumulation of these receptors in dopaminergic neurons, leading to neuronal death.3,4

In some hereditary degenerative dementias, gene mutations cause the aggregation of proteins, inhibiting proteasomal function involved in the processing of proteins and possibly causing neuronal death. Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) are frontotemporal dementias of autosomal dominant inheritance resulting from a gene mutation in the tau protein. Pathogenesis is thought to involve decreased metabolism of mutated tau in the proteasome.5α-Synuclein was identified as the causal gene of familial Parkinson's disease originating in south Italy.6 That report investigated the involvement of the accumulation of α-synuclein in the formation of Lewy bodies and the pathological process of Parkinson's disease. Huntington's disease occurs as a result of autosomal dominant inheritance, characterized by extension of the CAG repeat in Hantingtin.7 It was shown that extended CAG repeats also decreased proteasome function. As mentioned above, aggregation of aberrant proteins leading to inclusion formations due to dysfunction of UPS is the common process of neurodegerative dementia.

RELATIONSHIP BETWEEN UPS AND THE ENDOPLASMIC RETICULUM

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INCLUSION BODIES IN NEURODEGERATIVE DEMENTIAS
  5. MECHANISM OF UPS PROTEOLYSIS AND NEURODEGENERATIVE DEMENTIA
  6. RELATIONSHIP BETWEEN UPS AND THE ENDOPLASMIC RETICULUM
  7. CONCLUSION
  8. REFERENCES

Why does dysfunction of UPS following aggregation of abnormal proteins cause neuronal death/apoptosis?

The endoplasmic reticulum (ER) is the organelle involved in the correct control of protein folding and assembly by expression of molecular chaperones and is the site of other quality control systems for proteins. Thus, various types of stress to the ER cause accumulation of unfolded or misfolded proteins in the lumen of the ER. Because this disrupts ER homeostasis, the ER has developed highly specific signaling pathways, generally termed the ‘unfolded protein response’ (UPR). The UPR consists of three layers (Fig. 1). When mammalian cells are subjected to ER stress, the immediate response is activation of the double-stranded RNA-dependent protein kinase (PKR)-like ER-associated kinase (PERK), which inhibits protein biosynthesis through phosphorylation of eukaryotic translation initiation factor (eIF2α).8 Second, transcriptional induction of ER chaperones for refolding of unfolded proteins, such as Bip, is activated to alter transcriptional programs through inositol-requiring kinase 1 (IRE1) and X-box binding protein 1 (XBP-1).9 Third, unfolded or misfolded proteins in the ER lumen are retrotranslocated to the cytoplasm, where they are ubiquitinated and degraded by the proteasome. This process is called ER-associated degradation (ERAD).10 Via ERAD, there is a linkage between the ER and proteasome function. Thus, it is speculated that proteasome dysfunction may cause UPR followed by ER-mediated apoptosis, as described below.

image

Figure 1. The unfolded protein response (UPR). The UPR consists of three layers: transcriptional induction, translational attenuation and endoplasmic reticulum-associated degradation (ERAD). When mammalian cells are subjected to endoplasmic reticulum (ER) stress, the immediate response is activation of the double-stranded RNA-dependent protein kinase (PKR)-like ER-associated kinase (PERK) that inhibits protein biosynthesis through phosphorylation of eukaryotic translation initiation factor (eIF2α). Second, transcriptional induction of ER chaperones for refolding of unfolded proteins, such as Bip, is activated to alter transcriptional programs through inositol-requiring kinase 1 (IRE1) and X-box binding protein 1 (XBP-1). Third, unfolded or misfolded proteins in the ER lumen are retrotranslocated to the cytoplasm, where they are ubiquitinated and degraded by the proteasome. This process is called ERAD. If overload of unfolded or misfolded proteins in the ER is not resolved, prolonged UPR activation leads to apoptosis. The three known pro-apoptotic pathways emanating from the ER are mediated by IRE1, caspase-12 and C/EBP homologous protein (CHOP). Under ER stress, activated IRE1 recruits the cytosolic adapter tumor necrosis factor receptor-associated factor 2 (TRAF2) to the ER membrane and TRAF2 activates apoptosis-signaling kinase 1 (ASK1) to activate c-Jun amino-terminal kinase (JNK) for apoptosis. Caspase-12/4 is an ER-associated proximal effector of the caspase activation cascade and activates caspase-3, leading to apoptosis.

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If overload of unfolded or misfolded proteins in the ER is not resolved, prolonged UPR activation leads to apoptosis. Several previous studies analyzed apoptosis-related molecules centered around the mitochondria. However, it has been reported recently that some apoptotic processes originate in the ER.11,12 The three known pro-apoptotic pathways emanating from the ER are mediated by IRE1, caspase-12 and C/EBP homologous protein (CHOP), respectively (Fig. 1). Under ER stress, activated IRE1 recruits the cytosolic adapter tumor necrosis factor receptor-associated factor 2 (TRAF2) to the ER membrane.13 Then, TRAF2 activates apoptosis-signaling kinase 1 (ASK1) to activate c-Jun amino-terminal kinase (JNK) for apoptosis.12 Caspase-12 is an ER-associated proximal effector of the caspase activation cascade and activates caspase-3, leading to apoptosis.14 Because caspase-12 has been reported to be expressed in mice and rats,15 we screened a human colon cDNA library using the sequence of mouse caspase-12 as probe and detected caspase-4 with a high frequency.15 We also showed that caspase-4 was localized in the ER membrane and was strictly activated by ER stress inducers. Moreover, it was demonstrated that expression of caspase-4 was increased in AD brains. These findings suggest that caspase-4 may function as an ER stress response caspase in humans and may be involved in neuronal death in AD.15 A third death-signaling pathway activated by ER stress is mediated by transcriptional activation of genes encoding for pro-apoptotic functions. Activation of the UPR transducer PERK results in activation of the transcription of CHOP, a b-ZIP transcription factor that potentates apoptosis, possibly through repression of the expression of the apoptotic repressor BCL2.16

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INCLUSION BODIES IN NEURODEGERATIVE DEMENTIAS
  5. MECHANISM OF UPS PROTEOLYSIS AND NEURODEGENERATIVE DEMENTIA
  6. RELATIONSHIP BETWEEN UPS AND THE ENDOPLASMIC RETICULUM
  7. CONCLUSION
  8. REFERENCES

In most neurodegerative dementias, the pathogenesis remains unclear but characteristic inclusion bodies consisting of aberrant protein aggregation are observed. Recently, it has been clarified that these aberrant aggregations commonly involve UPS. It has also been shown that UPS is related to the UPR of the ER through ERAD. Therefore, in the present paper, we propose a hypothesis for the mechanism of neurodegerative dementia as follows: (i) aberrant protein aggregation overloads UPS; (ii) disturbed UPS suffers ERAD; (iii) disturbed ERAD impairs UPR; and (iv) prolonged UPR causes ER-mediated apoptosis. Based on this hypothesis, we can devise therapeutic strategies for each step of neurodegeration.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INCLUSION BODIES IN NEURODEGERATIVE DEMENTIAS
  5. MECHANISM OF UPS PROTEOLYSIS AND NEURODEGENERATIVE DEMENTIA
  6. RELATIONSHIP BETWEEN UPS AND THE ENDOPLASMIC RETICULUM
  7. CONCLUSION
  8. REFERENCES
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