Proteins Interplay in Neurodegeneration

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biomacromolecules: Proteins".

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 10449

Special Issue Editor


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Guest Editor
Department of Biotechnology Chemistry and Pharmacy, University of Siena, Siena, Italy
Interests: metalloprotein; metallopeptides; metal homeostasis; natural compounds; nutrients; oxidative stress; NMR spectroscopy

Special Issue Information

Dear Colleagues,

Several neurodegenerative diseases are associated with the extracellular or intracellular accumulation of protein inclusions regulated by a vast network of protein and metal interactions. Specific key proteins linked to neurodegeneration, such as amyloid-β, α-synuclein, islet amyloid polypeptide, and prion protein, share the ability to form toxic oligomeric and aggregate species. The precise mechanisms responsible for protein aggregation are still not clear; however, there is plenty of evidence indicating that metal ions, pH, membrane environments, ligand binding, and ionic strength might impact the aggregation rate. In addition to this, familial mutations and post-translational modifications might strongly affect the misfolding of aggregation-prone proteins. All these processes can induce novel or altered protein interactions, which in turn can impact numerous essential cellular processes, such as vesicle trafficking, altered metal homeostasis, cellular oxidative stress, and mitochondria dysfunction.

Dr. Daniela Valensin
Guest Editor

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Keywords

  • amyloidogenic proteins
  • metal ions
  • ROS
  • protein misfolding
  • neurons

Published Papers (5 papers)

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Research

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17 pages, 3657 KiB  
Article
PKN1 Exerts Neurodegenerative Effects in an In Vitro Model of Cerebellar Hypoxic–Ischemic Encephalopathy via Inhibition of AKT/GSK3β Signaling
by Stephanie zur Nedden, Motahareh Solina Safari, Friedrich Fresser, Klaus Faserl, Herbert Lindner, Bettina Sarg, Gottfried Baier and Gabriele Baier-Bitterlich
Biomolecules 2023, 13(11), 1599; https://doi.org/10.3390/biom13111599 - 31 Oct 2023
Cited by 1 | Viewed by 1051
Abstract
We recently identified protein kinase N1 (PKN1) as a negative gatekeeper of neuronal AKT protein kinase activity during postnatal cerebellar development. The developing cerebellum is specifically vulnerable to hypoxia-ischemia (HI), as it occurs during hypoxic-ischemic encephalopathy, a condition typically caused by oxygen deprivation [...] Read more.
We recently identified protein kinase N1 (PKN1) as a negative gatekeeper of neuronal AKT protein kinase activity during postnatal cerebellar development. The developing cerebellum is specifically vulnerable to hypoxia-ischemia (HI), as it occurs during hypoxic-ischemic encephalopathy, a condition typically caused by oxygen deprivation during or shortly after birth. In that context, activation of the AKT cell survival pathway has emerged as a promising new target for neuroprotective interventions. Here, we investigated the role of PKN1 in an in vitro model of HI, using postnatal cerebellar granule cells (Cgc) derived from Pkn1 wildtype and Pkn1−/− mice. Pkn1−/− Cgc showed significantly higher AKT phosphorylation, resulting in reduced caspase-3 activation and improved survival after HI. Pkn1−/− Cgc also showed enhanced axonal outgrowth on growth-inhibitory glial scar substrates, further pointing towards a protective phenotype of Pkn1 knockout after HI. The specific PKN1 phosphorylation site S374 was functionally relevant for the enhanced axonal outgrowth and AKT interaction. Additionally, PKN1pS374 shows a steep decrease during cerebellar development. In summary, we demonstrate the pathological relevance of the PKN1-AKT interaction in an in vitro HI model and establish the relevant PKN1 phosphorylation sites, contributing important information towards the development of specific PKN1 inhibitors. Full article
(This article belongs to the Special Issue Proteins Interplay in Neurodegeneration)
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15 pages, 2535 KiB  
Article
The Crystal Structure of the Hsp90-LA1011 Complex and the Mechanism by Which LA1011 May Improve the Prognosis of Alzheimer’s Disease
by S. Mark Roe, Zsolt Török, Andrew McGown, Ibolya Horváth, John Spencer, Tamás Pázmány, László Vigh and Chrisostomos Prodromou
Biomolecules 2023, 13(7), 1051; https://doi.org/10.3390/biom13071051 - 28 Jun 2023
Cited by 3 | Viewed by 1687
Abstract
Functional changes in chaperone systems play a major role in the decline of cognition and contribute to neurological pathologies, such as Alzheimer’s disease (AD). While such a decline may occur naturally with age or with stress or trauma, the mechanisms involved have remained [...] Read more.
Functional changes in chaperone systems play a major role in the decline of cognition and contribute to neurological pathologies, such as Alzheimer’s disease (AD). While such a decline may occur naturally with age or with stress or trauma, the mechanisms involved have remained elusive. The current models suggest that amyloid-β (Aβ) plaque formation leads to the hyperphosphorylation of tau by a Hsp90-dependent process that triggers tau neurofibrillary tangle formation and neurotoxicity. Several co-chaperones of Hsp90 can influence the phosphorylation of tau, including FKBP51, FKBP52 and PP5. In particular, elevated levels of FKBP51 occur with age and stress and are further elevated in AD. Recently, the dihydropyridine LA1011 was shown to reduce tau pathology and amyloid plaque formation in transgenic AD mice, probably through its interaction with Hsp90, although the precise mode of action is currently unknown. Here, we present a co-crystal structure of LA1011 in complex with a fragment of Hsp90. We show that LA1011 can disrupt the binding of FKBP51, which might help to rebalance the Hsp90-FKBP51 chaperone machinery and provide a favourable prognosis towards AD. However, without direct evidence, we cannot completely rule out effects on other Hsp90-co-chaprone complexes and the mechanisms they are involved in, including effects on Hsp90 client proteins. Nonetheless, it is highly significant that LA1011 showed promise in our previous AD mouse models, as AD is generally a disease affecting older patients, where slowing of disease progression could result in AD no longer being life limiting. The clinical value of LA1011 and its possible derivatives thereof remains to be seen. Full article
(This article belongs to the Special Issue Proteins Interplay in Neurodegeneration)
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15 pages, 3344 KiB  
Article
Distinct Effects of Familial Parkinson’s Disease-Associated Mutations on α-Synuclein Phase Separation and Amyloid Aggregation
by Bingkuan Xu, Fengshuo Fan, Yunpeng Liu, Yinghui Liu, Lin Zhou and Haijia Yu
Biomolecules 2023, 13(5), 726; https://doi.org/10.3390/biom13050726 - 23 Apr 2023
Cited by 6 | Viewed by 1890
Abstract
The Lewy bodies and Lewy neurites are key pathological hallmarks of Parkinson’s disease (PD). Single-point mutations associated with familial PD cause α-synuclein (α-Syn) aggregation, leading to the formation of Lewy bodies and Lewy neurites. Recent studies suggest α-Syn nucleates through liquid–liquid phase separation [...] Read more.
The Lewy bodies and Lewy neurites are key pathological hallmarks of Parkinson’s disease (PD). Single-point mutations associated with familial PD cause α-synuclein (α-Syn) aggregation, leading to the formation of Lewy bodies and Lewy neurites. Recent studies suggest α-Syn nucleates through liquid–liquid phase separation (LLPS) to form amyloid aggregates in a condensate pathway. How PD-associated mutations affect α-Syn LLPS and its correlation with amyloid aggregation remains incompletely understood. Here, we examined the effects of five mutations identified in PD, A30P, E46K, H50Q, A53T, and A53E, on the phase separation of α-Syn. All other α-Syn mutants behave LLPS similarly to wild-type (WT) α-Syn, except that the E46K mutation substantially promotes the formation of α-Syn condensates. The mutant α-Syn droplets fuse to WT α-Syn droplets and recruit α-Syn monomers into their droplets. Our studies showed that α-Syn A30P, E46K, H50Q, and A53T mutations accelerated the formation of amyloid aggregates in the condensates. In contrast, the α-Syn A53E mutant retarded the aggregation during the liquid-to-solid phase transition. Finally, we observed that WT and mutant α-Syn formed condensates in the cells, whereas the E46K mutation apparently promoted the formation of condensates. These findings reveal that familial PD-associated mutations have divergent effects on α-Syn LLPS and amyloid aggregation in the phase-separated condensates, providing new insights into the pathogenesis of PD-associated α-Syn mutations. Full article
(This article belongs to the Special Issue Proteins Interplay in Neurodegeneration)
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Review

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22 pages, 710 KiB  
Review
Current Technologies Unraveling the Significance of Post-Translational Modifications (PTMs) as Crucial Players in Neurodegeneration
by Saima Zafar, Shehzadi Irum Fatima, Matthias Schmitz and Inga Zerr
Biomolecules 2024, 14(1), 118; https://doi.org/10.3390/biom14010118 - 16 Jan 2024
Viewed by 2177
Abstract
Neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease, are identified and characterized by the progressive loss of neurons and neuronal dysfunction, resulting in cognitive and motor impairment. Recent research has shown the importance of PTMs, such as phosphorylation, acetylation, methylation, [...] Read more.
Neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease, are identified and characterized by the progressive loss of neurons and neuronal dysfunction, resulting in cognitive and motor impairment. Recent research has shown the importance of PTMs, such as phosphorylation, acetylation, methylation, ubiquitination, sumoylation, nitration, truncation, O-GlcNAcylation, and hydroxylation, in the progression of neurodegenerative disorders. PTMs can alter protein structure and function, affecting protein stability, localization, interactions, and enzymatic activity. Aberrant PTMs can lead to protein misfolding and aggregation, impaired degradation, and clearance, and ultimately, to neuronal dysfunction and death. The main objective of this review is to provide an overview of the PTMs involved in neurodegeneration, their underlying mechanisms, methods to isolate PTMs, and the potential therapeutic targets for these disorders. The PTMs discussed in this article include tau phosphorylation, α-synuclein and Huntingtin ubiquitination, histone acetylation and methylation, and RNA modifications. Understanding the role of PTMs in neurodegenerative diseases may provide new therapeutic strategies for these devastating disorders. Full article
(This article belongs to the Special Issue Proteins Interplay in Neurodegeneration)
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19 pages, 4415 KiB  
Review
Transmembrane Protein 175, a Lysosomal Ion Channel Related to Parkinson’s Disease
by Tuoxian Tang, Boshuo Jian and Zhenjiang Liu
Biomolecules 2023, 13(5), 802; https://doi.org/10.3390/biom13050802 - 9 May 2023
Cited by 5 | Viewed by 3162
Abstract
Lysosomes are membrane-bound organelles with an acidic lumen and are traditionally characterized as a recycling center in cells. Lysosomal ion channels are integral membrane proteins that form pores in lysosomal membranes and allow the influx and efflux of essential ions. Transmembrane protein 175 [...] Read more.
Lysosomes are membrane-bound organelles with an acidic lumen and are traditionally characterized as a recycling center in cells. Lysosomal ion channels are integral membrane proteins that form pores in lysosomal membranes and allow the influx and efflux of essential ions. Transmembrane protein 175 (TMEM175) is a unique lysosomal potassium channel that shares little sequence similarity with other potassium channels. It is found in bacteria, archaea, and animals. The prokaryotic TMEM175 consists of one six-transmembrane domain that adopts a tetrameric architecture, while the mammalian TMEM175 is comprised of two six-transmembrane domains that function as a dimer in lysosomal membranes. Previous studies have demonstrated that the lysosomal K+ conductance mediated by TMEM175 is critical for setting membrane potential, maintaining pH stability, and regulating lysosome–autophagosome fusion. AKT and B-cell lymphoma 2 regulate TMEM175’s channel activity through direct binding. Two recent studies reported that the human TMEM175 is also a proton-selective channel under normal lysosomal pH (4.5–5.5) as the K+ permeation dramatically decreased at low pH while the H+ current through TMEM175 greatly increased. Genome-wide association studies and functional studies in mouse models have established that TMEM175 is implicated in the pathogenesis of Parkinson’s disease, which sparks more research interests in this lysosomal channel. Full article
(This article belongs to the Special Issue Proteins Interplay in Neurodegeneration)
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