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The dark side of Alzheimer’s disease: unstructured biology of proteins from the amyloid cascade signaling pathway

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Abstract

Alzheimer’s disease (AD) is a leading cause of age-related dementia worldwide. Despite more than a century of intensive research, we are not anywhere near the discovery of a cure for this disease or a way to prevent its progression. Among the various molecular mechanisms proposed for the description of the pathogenesis and progression of AD, the amyloid cascade hypothesis, according to which accumulation of a product of amyloid precursor protein (APP) cleavage, amyloid β (Aβ) peptide, induces pathological changes in the brain observed in AD, occupies a unique niche. Although multiple proteins have been implicated in this amyloid cascade signaling pathway, their structure–function relationships are mostly unexplored. However, it is known that two major proteins related to AD pathology, Aβ peptide, and microtubule-associated protein tau belong to the category of intrinsically disordered proteins (IDPs), which are the functionally important proteins characterized by a lack of fixed, ordered three-dimensional structure. IDPs and intrinsically disordered protein regions (IDPRs) play numerous vital roles in various cellular processes, such as signaling, cell cycle regulation, macromolecular recognition, and promiscuous binding. However, the deregulation and misfolding of IDPs may lead to disturbed signaling, interactions, and disease pathogenesis. Often, molecular recognition-related IDPs/IDPRs undergo disorder-to-order transition upon binding to their biological partners and contain specific disorder-based binding motifs, known as molecular recognition features (MoRFs). Knowing the intrinsic disorder status and disorder-based functionality of proteins associated with amyloid cascade signaling pathway may help to untangle the mechanisms of AD pathogenesis and help identify therapeutic targets. In this paper, we have used multiple computational tools to evaluate the presence of intrinsic disorder and MoRFs in 27 proteins potentially relevant to the amyloid cascade signaling pathway. Among these, BIN1, APP, APOE, PICALM, PSEN1 and CD33 were found to be highly disordered. Furthermore, their disorder-based binding regions and associated short linear motifs have also been identified. These findings represent important foundation for the future research, and experimental characterization of disordered regions in these proteins is required to better understand their roles in AD pathogenesis.

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Abbreviations

AD:

Alzheimer’s disease

AICD:

APP intracellular domain

APP:

Amyloid precursor protein

Aβ:

Amyloid-beta

CD:

Cumulative distribution function

CH:

Charge-hydropathy

CME:

Clathrin-mediated endocytosis

CSF:

Cerebrospinal fluid

D2P2 :

Database of disordered protein predictions

ELM:

Eukaryotic linear motifs

FAD:

Familial Alzheimer’s disease

GWAS:

Genome-wide association studies

HDL:

High-density lipoprotein

IDP:

Intrinsically disordered proteins

IDPRs:

Intrinsically disordered protein regions

ITAM:

Immunotyrosine inhibitory motif

LDLR:

Low-density lipoprotein receptor

LOAD:

Late onset of Alzheimer’s disease

MCI:

Mild cognitive impairment

MoRFs:

Molecular recognition features

NFT:

Neurofibrillary tangles

NMDA:

N-Methyl-d-aspartate

PONDR:

Predictor of natural disordered regions

PPID:

Predicted percentage of intrinsic disorder

PTM:

Post-translational modification

SIGLECs:

Sialic acid-binding Ig-like family

SLiM:

Short linear motifs

STRING:

Search tool for retrieval of interacting genes

TGN:

Trans-Golgi network

TNF:

Tumor necrotic factor

tPA:

Tissue plasminogen activator

uPA:

Urokinase PLG activator

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Acknowledgements

RG and KG are supported by the DBT project (BT/PR16871/NER/95/329/201). BG is grateful to DBT-IUSSTF sponsored Khorana scholarship 2019. PK would like to thank DBT for funding (BT/IN/IC-Impacts/21/DS/2016-2017). VU and RG are thankful to MHRD-SPARC (SPARC/2018-2019/P37/SL).

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Authors and Affiliations

  1. School of Basic Sciences, Indian Institute of Technology Mandi, Mandi, India

    Kundlik Gadhave, Bhuvaneshwari R. Gehi, Prateek Kumar & Rajanish Giri

  2. Department of Cell Biology, Microbiology and Molecular Biology, School of Natural Sciences and Mathematics, College of Arts and Sciences, University of South Florida, Tampa, FL, 33620, USA

    Bin Xue

  3. Department of Molecular Medicine and Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, 33620, USA

    Vladimir N. Uversky

  4. Laboratory of New Methods in Biology, Institute for Biological Instrumentation, Russian Academy of Sciences, 142290, Pushchino, Moscow Region, Russia

    Vladimir N. Uversky

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  1. Kundlik Gadhave
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  4. Bin Xue
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  5. Vladimir N. Uversky
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RG and VNU conception, design and study supervision; KG, PG, BG, BX, VNU, and RG produced and analyzed data; KG, BG, VNU, and RG wrote and edited the manuscript.

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Correspondence to Vladimir N. Uversky or Rajanish Giri.

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Gadhave, K., Gehi, B.R., Kumar, P. et al. The dark side of Alzheimer’s disease: unstructured biology of proteins from the amyloid cascade signaling pathway. Cell. Mol. Life Sci. 77, 4163–4208 (2020). https://doi.org/10.1007/s00018-019-03414-9

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