Unfolded protein response is activated in <scp>L</scp>ewy body dementias

Baek, Jean-Ha; Whitfield, David; Howlett, David; Francis, Paul T.; Bereczki, Erika; Ballard, Clive; Hortobágyi, Tibor; Attems, Johannes; Aarsland, Dag

doi:10.1111/nan.12260

Cited by 45 publications

(38 citation statements)

References 48 publications

(64 reference statements)

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“…The roles of these as well as other potentially relevant mechanisms for cognitive impairment, such as the unfolded protein response 51 , the ubiquitin–proteasome system 52 , and increased neurogenesis (for example, in response to neurotrophic factors) 53 , need to be explored further (see Management section below).…”

Section: Mechanismsmentioning

confidence: 99%

Cognitive decline in Parkinson disease

et al. 2017

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Dementia is a frequent problem encountered in advanced stages of Parkinson disease (PD). In recent years, research has focused on the pre-dementia stages of cognitive impairment in PD, including mild cognitive impairment (MCI). Several longitudinal studies have shown that MCI is a harbinger of dementia in PD, although the course is variable, and stabilization of cognition — or even reversal to normal cognition — is not uncommon. In addition to limbic and cortical spread of Lewy pathology, several other mechanisms are likely to contribute to cognitive decline in PD, and a variety of biomarker studies, some using novel structural and functional imaging techniques, have documented in vivo brain changes associated with cognitive impairment. The evidence consistently suggests that low cerebrospinal fluid levels of amyloid-β42, a marker of comorbid Alzheimer disease (AD), predict future cognitive decline and dementia in PD. Emerging genetic evidence indicates that in addition to the APOE*ε4 allele (an established risk factor for AD), GBA mutations and SCNA mutations and triplications are associated with cognitive decline in PD, whereas the findings are mixed for MAPT polymorphisms. Cognitive enhancing medications have some effect in PD dementia, but no convincing evidence that progression from MCI to dementia can be delayed or prevented is available, although cognitive training has shown promising results.

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Section: Mechanismsmentioning

confidence: 99%

Cognitive decline in Parkinson disease

et al. 2017

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“…In Parkinson’s disease, elevated expression of BiP and other UPR proteins have been reported in many cellular and animal models of Parkinson’s disease (Baek et al, 2016). Interestingly, the SH-SY5Y cell model exhibited lower BiP mRNA levels when treated with the neurotoxin 1-methyl-4-phenylpyridinium (MPP+); however, treating the same cell model with 6-hydroxydopamine, another Parkinson’s disease inducer, raised BiP mRNA levels.…”

Section: Clinical Significancementioning

confidence: 99%

HSPA5 Gene encoding Hsp70 chaperone BiP in the endoplasmic reticulum

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et al. 2017

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The HSPA5 gene (Ensembl ID: ENSG00000044574 (WTSI/EMBL-EBI, 2015)) encodes the binding immunoglobulin protein (BiP), an Hsp70 family chaperone localized in the ER lumen. As a highly conserved molecular chaperone, BiP assists in a wide range of folding processes via its two structural domains, a nucleotide-binding domain (NBD) and substrate-binding domain (SBD). BiP is also an essential component of the translocation machinery for protein import into the ER, a regulator for Ca2+ homeostasis in the ER, as well as a facilitator of ER-associated protein degradation (ERAD) via retrograde transportation of aberrant proteins across the ER membrane. When unfolded/misfolded proteins in the ER overwhelm the capacity of protein folding machinery, BiP can initiate the unfolded protein response (UPR), decrease unfolded/misfolded protein load, induce autophagy, and crosstalk with apoptosis machinery to assist in the cell survival decision. Post- translational modifications (PTMs) of BiP have been shown to regulate BiP’s activity, turnover, and availability upon different extrinsic or intrinsic stimuli. As a master regulator of ER function, BiP is associated with cancer, cardiovascular disease, neurodegenerative disease, and immunological diseases. BiP has been targeted in cancer therapies and shows promise for application in other relevant diseases.

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“…Additional molecular alterations converge in the pathogenesis of DLB, including impaired autophagy and ubiquitin-proteasome system of protein (46–50), as well as altered responses to protein misfolding (51). Preliminary studies have shown impaired mitochondrial activity and oxidative damage involving proteins, lipids, and DNA in the neocortex in DLB (52, 53); α-synuclein is one of the targets of oxidative damage in the frontal cortex in DLB (54).…”

Section: Introductionmentioning

confidence: 99%

Dementia with Lewy Bodies: Molecular Pathology in the Frontal Cortex in Typical and Rapidly Progressive Forms

et al. 2017

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ObjectivesThe goal of this study was to assess mitochondrial function, energy, and purine metabolism, protein synthesis machinery from the nucleolus to the ribosome, inflammation, and expression of newly identified ectopic olfactory receptors (ORs) and taste receptors (TASRs) in the frontal cortex of typical cases of dementia with Lewy bodies (DLB) and cases with rapid clinical course (rpDLB: 2 years or less) compared with middle-aged non-affected individuals, in order to learn about the biochemical abnormalities underlying Lewy body pathology.MethodsReal-time quantitative PCR, mitochondrial enzymatic assays, and analysis of β-amyloid, tau, and synuclein species were used.ResultsThe main alterations in DLB and rpDLB, which are more marked in the rapidly progressive forms, include (i) deregulated expression of several mRNAs and proteins of mitochondrial subunits, and reduced activity of complexes I, II, III, and IV of the mitochondrial respiratory chain; (ii) reduced expression of selected molecules involved in energy metabolism and increased expression of enzymes involved in purine metabolism; (iii) abnormal expression of nucleolar proteins, rRNA18S, genes encoding ribosomal proteins, and initiation factors of the transcription at the ribosome; (iv) discrete inflammation; and (v) marked deregulation of brain ORs and TASRs, respectively. Severe mitochondrial dysfunction involving activity of four complexes, minimal inflammatory responses, and dramatic altered expression of ORs and TASRs discriminate DLB from Alzheimer’s disease. Altered solubility and aggregation of α-synuclein, increased β-amyloid bound to membranes, and absence of soluble tau oligomers are common in DLB and rpDLB. Low levels of soluble β-amyloid are found in DLB. However, increased soluble β-amyloid 1–40 and β-amyloid 1–42, and increased TNFα mRNA and protein expression, distinguish rpDLB.ConclusionMolecular alterations in frontal cortex in DLB involve key biochemical pathways such as mitochondria and energy metabolism, protein synthesis, purine metabolism, among others and are accompanied by discrete innate inflammatory response.

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Unfolded protein response is activated in Lewy body dementias

Cited by 45 publications

References 48 publications

Cognitive decline in Parkinson disease

Cognitive decline in Parkinson disease

HSPA5 Gene encoding Hsp70 chaperone BiP in the endoplasmic reticulum

Dementia with Lewy Bodies: Molecular Pathology in the Frontal Cortex in Typical and Rapidly Progressive Forms

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