bims-proned 2023-12-24 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2023–12–24
fourteen papers selected by
Verena Kohler, Umeå University

A tale of dual functions of SERF family proteins in regulating amyloid formation.
Comprehensive mapping of mutations in TDP-43 and α-Synuclein that affect stability and binding.
Recombinant Full-Length TDP-43 Oligomers Retain Their Ability to Bind RNAs, Are Not Toxic, and Do Not Seed TDP-43 Aggregation in Vitro.
Saccharomyces cerevisiae as a Model for Studying Human Neurodegenerative Disorders: Viral Capsid Protein Expression.
Immunization Effects of a Novel α-Synuclein-Based Peptide Epitope Vaccine in Parkinson's Disease-Associated Pathology.
Relationship among α‑synuclein, aging and inflammation in Parkinson's disease (Review).
Impaired neuronal activity as a potential factor contributing to the underdeveloped cerebrovasculature in a young Parkinson's disease mouse model.
Highly Potent Peptide Therapeutics To Prevent Protein Aggregation in Huntington's Disease.
Molecular Chaperones as Therapeutic Target: Hallmark of Neurodegenerative Disorders.
The autophagy of stress granules.
Targeting RACK1 to alleviate TDP-43 and FUS proteinopathy-mediated suppression of protein translation and neurodegeneration.
Preventing amyloid-β oligomerization and aggregation with berberine: Investigating the mechanism of action through computational methods.
Elucidation of Site-Specific Ubiquitination on Chaperones in Response to Mutant Huntingtin.
Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases.

Chembiochem. 2023 Dec 15. e202300727

A tale of dual functions of SERF family proteins in regulating amyloid formation.

Shixing Qi, Yun Peng, Guan Wang, Xu Zhang, Maili Liu, Lichun He.

  The abnormal aggregation of proteins is a significant pathological hallmark of diseases, such as the amyloid formation associated with fused in sarcoma protein (FUS) in frontotemporal lobar degeneration and amyotrophic lateral sclerosis diseases. Understanding which cellular components and how these components regulate the process of abnormal protein aggregation in living organisms is crucial for the prevention and treatment of neurodegenerative diseases. MOAG-4/SERF is a conserved family of proteins with rich positive charged residues, which was initially identified as an enhancer for the formation of amyloids in C. elegans. Knocking out SERF impedes the amyloid formation of various proteins, including α-synuclein and β-amyloid, which are linked to Parkinson's and Alzheimer's diseases, respectively. However, recent studies revealed SERF exhibited dual functions, as it could both promote and inhibit the fibril formation of the neurodegenerative disease-related amyloidogenic proteins. The connection between functions and structure basis of SERF in regulating the amyloid formation is still unclear. This review will outline the hallmark proteins in neurodegenerative diseases, summarize the contradictory role of the SERF protein family in promoting and inhibiting the aggregation of neurodegenerative proteins, and finally explore the potential structural basis and functional selectivity of the SERF protein.

Keywords:  SERF * MOAG-4 * Neurodegenerative Disease * Amyloidogenic Protein* Protein Aggregation

DOI:  https://doi.org/10.1002/cbic.202300727
J Biomol Struct Dyn. 2023 Dec 21. 1-13

Comprehensive mapping of mutations in TDP-43 and α-Synuclein that affect stability and binding.

Sultan Alamri, Shafiul Haque, Badra S Alghamdi, Haythum O Tayeb, Shereen Azhari, Reem M Farsi, Abear Elmokadem, Turki Alamri, Steve Harakeh, Amresh Prakash, Vijay Kumar.

  Abnormal aggregation and amyloid inclusions of TAR DNA-binding protein 43 (TDP-43) and α-Synuclein (α-Syn) are frequently co-observed in amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Several reports showed TDP-43 C-terminal domain (CTD) and α-Syn interact with each other and the aggregates of these two proteins colocalized together in different cellular and animal models. Molecular dynamics simulation was conducted to elucidate the stability of the TDP-43 and Syn complex structure. The interfacial mutations in protein complexes changes the stability and binding affinity of the protein that may cause diseases. Here, we have utilized the computational saturation mutagenesis approach including structure-based stability and binding energy calculations to compute the systemic effects of missense mutations of TDP-43 CTD and α-Syn on protein stability and binding affinity. Most of the interfacial mutations of CTD and α-Syn were found to destabilize the protein and reduced the protein binding affinity. The results thus shed light on the functional consequences of missense mutations observed in TDP-43 associated proteinopathies and may provide the mechanisms of co-morbidities involving these two proteins.Communicated by Ramaswamy H. Sarma.

Keywords:  TDP-43 CTD; binding affinity; missense mutations; protein interface; stability; α-Synuclein

DOI:  https://doi.org/10.1080/07391102.2023.2293258
ACS Chem Neurosci. 2023 Dec 20.

Recombinant Full-Length TDP-43 Oligomers Retain Their Ability to Bind RNAs, Are Not Toxic, and Do Not Seed TDP-43 Aggregation in Vitro.

Lixin Yang, Yllza Jasiqi, Hilal Lashuel.

  TAR DNA-binding protein with 43 kD (TDP-43) is a partially disordered protein that misfolds and accumulates in the brains of patients affected by several neurodegenerative diseases. TDP-43 oligomers have been reported to form due to aberrant misfolding or self-assembly of TDP-43 monomers. However, very little is known about the molecular and structural basis of TDP-43 oligomerization and the toxic properties of TDP-43 oligomers due to several reasons, including the lack of conditions available for isolating native TDP-43 oligomers or producing pure TDP-43 oligomers in sufficient quantities for biophysical, cellular, and in vivo studies. To address these challenges, we developed new protocols to generate different stable forms of unmodified and small-molecule-induced TDP-43 oligomers. Our results showed that co-incubation of TDP-43 with small molecules, such as epigallocatechin gallate (EGCG), dopamine, and 4-hydroxynonenal (4-HNE), increased the production yield of TDP-43 stable oligomers, which could be purified by size-exclusion chromatography. Interestingly, despite significant differences in the morphology and size distribution of the TDP-43 oligomer preparations revealed by transmission electron microscopy (TEM) and dynamic light scattering (DLS), they all retained the ability to bind to nucleotide DNA. Besides, circular dichroism (CD) analysis of these oligomers did not show much difference in the secondary structure composition. Surprisingly, none of these oligomer preparations could seed the aggregation of TDP-43 core peptide 279-360. Finally, we showed that all four types of TDP-43 oligomers exert very mild cytotoxicity to primary neurons. Collectively, our results suggest that functional TDP-43 oligomers can be selectively stabilized by small-molecule compounds. This strategy may offer a new approach to halt TDP-43 aggregation in various proteinopathies.

Keywords:  Neurodegenerative diseases; TDP-43 oligomers; aggregation; cytotoxicity; seeding

DOI:  https://doi.org/10.1021/acschemneuro.3c00691
Int J Mol Sci. 2023 Dec 07. pii: 17213. [Epub ahead of print]24(24):

Saccharomyces cerevisiae as a Model for Studying Human Neurodegenerative Disorders: Viral Capsid Protein Expression.

Svetlana V Bayandina, Dmitry V Mukha.

  In this article, we briefly describe human neurodegenerative diseases (NDs) and the experimental models used to study them. The main focus is the yeast Saccharomyces cerevisiae as an experimental model used to study neurodegenerative processes. We review recent experimental data on the aggregation of human neurodegenerative disease-related proteins in yeast cells. In addition, we describe the results of studies that were designed to investigate the molecular mechanisms that underlie the aggregation of reporter proteins. The advantages and disadvantages of the experimental approaches that are currently used to study the formation of protein aggregates are described. Special attention is given to the similarity between aggregates that form as a result of protein misfolding and viral factories-special structural formations in which viral particles are formed inside virus-infected cells. A separate part of the review is devoted to our previously published study on the formation of aggregates upon expression of the insect densovirus capsid protein in yeast cells. Based on the reviewed results of studies on NDs and related protein aggregation, as well as viral protein aggregation, a new experimental model system for the study of human NDs is proposed. The core of the proposed system is a comparative transcriptomic analysis of changes in signaling pathways during the expression of viral capsid proteins in yeast cells.

Keywords:  CytoQ; INQ; IPOD; JUNQ; Saccharomyces cerevisiae; capsid virus proteins; neurodegenerative diseases; protein aggregation; transcriptional regulatory pathways; virus factories

DOI:  https://doi.org/10.3390/ijms242417213
Vaccines (Basel). 2023 Dec 05. pii: 1820. [Epub ahead of print]11(12):

Immunization Effects of a Novel α-Synuclein-Based Peptide Epitope Vaccine in Parkinson's Disease-Associated Pathology.

Jun Sung Park, Riaz Ahmad, Kyonghwan Choe, Min Hwa Kang, Tae Ju Park, Myeong Ok Kim.

  Parkinson's disease (PD) is a chronic neurodegenerative disease that affects the central nervous system, specifically the motor system. It is mainly caused by the loss of dopamine due to the accumulation of α-synuclein (α-syn) protein in the striatum and substantia nigra pars compacta (SNpc). Previous studies have reported that immunization may be a potential preventive strategy for neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Therefore, the aim of the study was to design an α-syn specific epitope vaccine and investigate its effect in PD-related pathophysiology using an α-syn-induced mouse model. We used an in silico model to identify and design a non-toxic α-syn-based peptide epitope vaccine and, to overcome poor immunogenicity, the vaccine was coupled with immunogenic carrier proteins, i.e., ovalbumin (OVA) and keyhole limpet haemocyanin (KLH). Our results showed that vaccinated PD mouse models, especially with vaccines with carrier proteins, improved in motor functions compared with the non-vaccinated PD model. Additionally, the vaccinated groups showed increased immunoglobulin G (IgG) levels in the spleen and plasma as well as decreased interleukin-10 (IL-10) levels in the plasma. Furthermore, vaccinated groups, especially OVA and KLH groups, showed decrease in α-syn levels and increased dopamine-related markers, i.e., tyrosine hydroxylase (TH), vesicle monoamine transporter 2 (VMAT2), and dopamine transporter (DAT), and autophagy activities in the striatum and SNpc. Lastly, our data showed decreased neuroinflammation by reducing the activation of microglia and astrocytes and pro-inflammatory cytokines in the immunized groups, especially with OVA and KLH carrier proteins. Overall, these results suggest that vaccination, especially with immunogenic carrier proteins, is effective in reducing the accumulation of α-syn aggregates in the brain and ameliorate PD-related pathophysiology. Hence, further development of this approach might have a potential role in preventing the development of PD.

Keywords:  Parkinson’s disease (PD); epitope; immunization; neuroinflammation; α-synuclein

DOI:  https://doi.org/10.3390/vaccines11121820
Exp Ther Med. 2024 Jan;27(1): 23

Relationship among α‑synuclein, aging and inflammation in Parkinson's disease (Review).

Nianping Zhang, Zhaoli Yan, Hua Xin, Shuai Shao, Song Xue, Raymond Cespuglio, Shijun Wang.

  Parkinson's disease (PD) is a common neurodegenerative pathology whose major clinical symptoms are movement disorders. The main pathological characteristics of PD are the selective death of dopaminergic (DA) neurons in the pars compacta of the substantia nigra and the presence of Lewy bodies containing α-synuclein (α-Syn) within these neurons. PD is associated with numerous risk factors, including environmental factors, genetic mutations and aging. In many cases, the complex interplay of numerous risk factors leads to the onset of PD. The mutated α-Syn gene, which expresses pathologicalα-Syn protein, can cause PD. Another important feature of PD is neuroinflammation, which is conducive to neuronal death. α-Syn is able to interact with certain cell types in the brain, including through phagocytosis and degradation of α-Syn by glial cells, activation of inflammatory pathways by α-Syn in glial cells, transmission of α-Syn between glial cells and neurons, and interactions between peripheral immune cells and α-Syn. In addition to the aforementioned risk factors, PD may also be associated with aging, as the prevalence of PD increases with advancing age. The aging process impairs the cellular clearance mechanism, which leads to chronic inflammation and the accumulation of intracellular α-Syn, which results in DA neuronal death. In the present review, the age-associated α-Syn pathogenicity and the interactions between α-Syn and certain types of cells within the brain are discussed to facilitate understanding of the mechanisms of PD pathogenesis, which may potentially provide insight for the future clinical treatment of PD.

Keywords:  Parkinson's disease; aging; alpha-synuclein; astrocytes; dopaminergic neurons; microglia; neurodegenerative disorder; neuroinflammation; oligodendrocytes; peripheral immune cells

DOI:  https://doi.org/10.3892/etm.2023.12311
Sci Rep. 2023 Dec 18. 13(1): 22613

Impaired neuronal activity as a potential factor contributing to the underdeveloped cerebrovasculature in a young Parkinson's disease mouse model.

Jin-Young Jeong, Hyun Jung Lee, Namsuk Kim, Yan Li, Jong-Cheol Rah, Won-Jong Oh.

Misfolding of α-synuclein (α-Syn) in the brain causes cellular dysfunction, leading to cell death in a group of neurons, and consequently causes the progression of Parkinson's disease (PD). Although many studies have demonstrated the pathological connections between vascular dysfunction and neurodegenerative diseases, it remains unclear how neuronal accumulation of α-Syn affects the structural and functional aspects of the cerebrovasculature to accelerate early disease progression. Here, we demonstrated the effect of aberrant α-Syn expression on the brain vasculature using a PD mouse model expressing a familial mutant form of human α-Syn selectively in neuronal cells. We showed that young PD mice have an underdeveloped cerebrovasculature without significant α-Syn accumulation in the vasculature. During the early phase of PD, toxic α-Syn was selectively increased in neuronal cells, while endothelial cell proliferation was decreased in the absence of vascular cell death or neuroinflammation. Instead, we observed altered neuronal activation and minor changes in the activity-dependent gene expression in brain endothelial cells (ECs) in young PD mice. These findings demonstrated that neuronal expression of mutant α-Syn in the early stage of PD induces abnormal neuronal activity and contributes to vascular patterning defects, which could be associated with a reduced angiogenic potential of ECs.

DOI: https://doi.org/10.1038/s41598-023-49900-w
ACS Med Chem Lett. 2023 Dec 14. 14(12): 1821-1826

Highly Potent Peptide Therapeutics To Prevent Protein Aggregation in Huntington's Disease.

Anooshay Khan, Cemile Elif Özçelik, Ozge Begli, Oguzhan Oguz, Mehmet Seçkin Kesici, Talip Serkan Kasırga, Salih Özçubukcu, Esra Yuca, Urartu Ozgur Safak Seker.

Huntington's disease (HD) is a neurodegenerative disorder resulting from a significant amplification of CAG repeats in exon 1 of the Huntingtin (Htt) gene. More than 36 CAG repeats result in the formation of a mutant Htt (mHtt) protein. These amino-terminal mHtt fragments lead to the formation of misfolded proteins, which then form aggregates in the relevant brain regions. Therapies that can delay the progression of the disease are imperative to halting the course of the disease. Peptide-based drug therapies provide such a platform. Inhibitory peptides were screened against monomeric units of both wild type (Htt(Q25)) and mHtt fragments, Htt(Q46) and Htt(Q103). Fibril kinetics was studied by utilizing the Thioflavin T (ThT) assay. Atomic force microscopy was also used to study the influence of the peptides on fibril formation. These experiments demonstrate that the chosen peptides suppress the formation of fibrils in mHtt proteins and can provide a therapeutic lead for further optimization and development.

DOI: https://doi.org/10.1021/acsmedchemlett.3c00415
Mol Neurobiol. 2023 Dec 21.

Molecular Chaperones as Therapeutic Target: Hallmark of Neurodegenerative Disorders.

Aditi Sharma, Om Prakash Shah, Lalit Sharma, Monica Gulati, Tapan Behl, Asaad Khalid, Syam Mohan, Asim Najmi, Khalid Zoghebi.

  Misfolded and aggregated proteins build up in neurodegenerative illnesses, which causes neuronal dysfunction and ultimately neuronal death. In the last few years, there has been a significant upsurge in the level of interest towards the function of molecular chaperones in the control of misfolding and aggregation. The crucial molecular chaperones implicated in neurodegenerative illnesses are covered in this review article, along with a variety of their different methods of action. By aiding in protein folding, avoiding misfolding, and enabling protein breakdown, molecular chaperones serve critical roles in preserving protein homeostasis. By aiding in protein folding, avoiding misfolding, and enabling protein breakdown, molecular chaperones have integral roles in preserving regulation of protein balance. It has been demonstrated that aging, a significant risk factor for neurological disorders, affects how molecular chaperones function. The aggregation of misfolded proteins and the development of neurodegeneration may be facilitated by the aging-related reduction in chaperone activity. Molecular chaperones have also been linked to the pathophysiology of several instances of neuron withering illnesses, enumerating as Parkinson's disease, Huntington's disease, and Alzheimer's disease. Molecular chaperones have become potential therapy targets concerning with the prevention and therapeutic approach for brain disorders due to their crucial function in protein homeostasis and their connection to neurodegenerative illnesses. Protein homeostasis can be restored, and illness progression can be slowed down by methods that increase chaperone function or modify their expression. This review emphasizes the importance of molecular chaperones in the context of neuron withering disorders and their potential as therapeutic targets for brain disorders.

Keywords:  Heat shock protein; Molecular chaperones; Neurodegeneration; Ubiquitin-substrate conjugate

DOI:  https://doi.org/10.1007/s12035-023-03846-2
FEBS Lett. 2023 Dec 15.

The autophagy of stress granules.

Laura Ryan, David C Rubinsztein.

  Our understanding of stress granule (SG) biology has deepened considerably in recent years, and with this, increased understanding of links has been made between SGs and numerous neurodegenerative diseases. One of the proposed mechanisms by which SGs and any associated protein aggregates may become pathological is based upon defects in their autophagic clearance, and so the precise processes governing the degradation of SGs are important to understand. Mutations and disease-associated variants implicated in amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and frontotemporal lobar dementia compromise autophagy, whilst autophagy-inhibiting drugs or knockdown of essential autophagy proteins result in the persistence of SGs. In this review, we will consider the current knowledge regarding the autophagy of SG.

Keywords:  P62; amyotrophic lateral sclerosis; autophagy; granulophagy; neurodegeneration; proteostasis; stress granules; valosin-containing protein

DOI:  https://doi.org/10.1002/1873-3468.14787
Acta Neuropathol Commun. 2023 Dec 18. 11(1): 200

Targeting RACK1 to alleviate TDP-43 and FUS proteinopathy-mediated suppression of protein translation and neurodegeneration.

Beibei Zhao, Catherine M Cowan, Juliane A Coutts, Darren D Christy, Ananya Saraph, Shawn C C Hsueh, Stephen S Plotkin, Ian R Mackenzie, Johanne M Kaplan, Neil R Cashman.

TAR DNA-binding protein 43 (TDP-43) and Fused in Sarcoma/Translocated in Sarcoma (FUS) are ribonucleoproteins associated with pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Under physiological conditions, TDP-43 and FUS are predominantly localized in the nucleus, where they participate in transcriptional regulation, RNA splicing and metabolism. In disease, however, they are typically mislocalized to the cytoplasm where they form aggregated inclusions. A number of shared cellular pathways have been identified that contribute to TDP-43 and FUS toxicity in neurodegeneration. In the present study, we report a novel pathogenic mechanism shared by these two proteins. We found that pathological FUS co-aggregates with a ribosomal protein, the Receptor for Activated C-Kinase 1 (RACK1), in the cytoplasm of spinal cord motor neurons of ALS, as previously reported for pathological TDP-43. In HEK293T cells transiently transfected with TDP-43 or FUS mutant lacking a functional nuclear localization signal (NLS; TDP-43ΔNLS and FUSΔNLS), cytoplasmic TDP-43 and FUS induced co-aggregation with endogenous RACK1. These co-aggregates sequestered the translational machinery through interaction with the polyribosome, accompanied by a significant reduction of global protein translation. RACK1 knockdown decreased cytoplasmic aggregation of TDP-43ΔNLS or FUSΔNLS and alleviated associated global translational suppression. Surprisingly, RACK1 knockdown also led to partial nuclear localization of TDP-43ΔNLS and FUSΔNLS in some transfected cells, despite the absence of NLS. In vivo, RACK1 knockdown alleviated retinal neuronal degeneration in transgenic Drosophila melanogaster expressing hTDP-43WT or hTDP-43Q331K and improved motor function of hTDP-43WT flies, with no observed adverse effects on neuronal health in control knockdown flies. In conclusion, our results revealed a novel shared mechanism of pathogenesis for misfolded aggregates of TDP-43 and FUS mediated by interference with protein translation in a RACK1-dependent manner. We provide proof-of-concept evidence for targeting RACK1 as a potential therapeutic approach for TDP-43 or FUS proteinopathy associated with ALS and FTLD.

DOI: https://doi.org/10.1186/s40478-023-01705-8
Int J Biol Macromol. 2023 Dec 19. pii: S0141-8130(23)05799-9. [Epub ahead of print] 128900

Preventing amyloid-β oligomerization and aggregation with berberine: Investigating the mechanism of action through computational methods.

Faizan Abul Qais, Nagma Parveen, Mohd Afzal, Mohammad Furkan, Rizwan Hasan Khan.

  Neurological disorders (NDs) have become a major cause of both cognitive and physical disabilities worldwide. In NDs, misfolded proteins tend to adopt a β-sheet-rich fibrillar structure called amyloid. Amyloid beta (Aβ) plays a crucial role in the nervous system. The misfolding and aggregation of Aβ are primary factors in the progression of Alzheimer's disease (AD). Inhibiting the oligomerization and aggregation of Aβ is considered as an effective strategy against NDs. While it is known that berberine analogs exhibit anti-Aβ aggregation properties, the precise mechanism of action remains unclear. In this study, we have employed computational approaches to unravel the possible mechanism by which berberine combats Aβ aggregation. The introduction of berberine was observed to delay the equilibrium of Aβ16-21 oligomerization. Initially, within the first 10 ns of simulation, β-sheets content was 12.89 % and gradually increased to 22.19 % within the first 20 ns. This upward trend continued, reaching 32.80 %. However, berberine substantially reduced the formation of β-sheets to 1.36 %. These findings decipher the potency of berberine against Aβ16-21 oligomerization, a crucial step for β-sheet formation. Additionally, a remarkable decrease in total number of hydrogen bonds was found in the presence of berberine. Berberine also led to a slight reduction in the flexibility of Aβ16-21, which may be due to the formation of a more stable structures. This study offers valuable insights at the mechanistic level, which could prove beneficial in the development of new drugs to combat NDs.

Keywords:  Aggregation; Amyloid beta; Berberine; Molecular dynamics simulation; Oligomerization

DOI:  https://doi.org/10.1016/j.ijbiomac.2023.128900
Cell Mol Neurobiol. 2023 Dec 15. 44(1): 3

Elucidation of Site-Specific Ubiquitination on Chaperones in Response to Mutant Huntingtin.

Prajnadipta Panda, Vivek Sarohi, Trayambak Basak, Prasad Kasturi.

  Huntington's disease (HD) is one of the prominent neurodegenerative diseases, characterized by the progressive decline of neuronal function, due to the accumulation and aggregation of misfolded proteins. Pathological progression of HD is hallmarked by the aberrant aggregation of the huntingtin protein (HTT) and subsequent neurotoxicity. Molecular chaperones (heat shock proteins, HSPs) play a pivotal role in maintaining proteostasis by facilitating protein refolding, degradation, or sequestration to limit the accumulation of misfolded proteins during neurotoxicity. However, the role of post-translational modifications such as ubiquitination among HSPs during HD is less known. In this study, we aimed to elucidate HSPs ubiquitin code in the context of HD pathogenesis. In a comprehensive proteomic analysis, we identified site-specific ubiquitination events in HSPs associated with HTT in HD-affected brain regions. To assess the impact of ubiquitination on HSPs during HD, we quantified the abundance of ubiquitinated lysine sites in both the rat cortex/striatum and in the mouse primary cortical neurons. Strikingly, we observed highly tissue-specific alterations in the relative ubiquitination levels of HSPs under HD conditions, emphasizing the importance of spatial perturbed post-translational modifications (PTMs) in shaping disease pathology. These ubiquitination events, combined with other PTMs on HSPs, are likely to influence the phase transitions of HTT. In conclusion, our study uncovered differential site-specific ubiquitination of molecular chaperones and offers a comprehensive view of the intricate relationship between protein aggregation, and PTMs in the context of Huntington's disease.

Keywords:  Huntington's disease; Molecular chaperones; Posttranslational modifications; Proteomics

DOI:  https://doi.org/10.1007/s10571-023-01446-1
Biomolecules. 2023 Dec 13. pii: 1789. [Epub ahead of print]13(12):

Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases.

Paula Cilleros-Holgado, David Gómez-Fernández, Rocío Piñero-Pérez, Jose Manuel Romero-Domínguez, Diana Reche-López, Alejandra López-Cabrera, Mónica Álvarez-Córdoba, Manuel Munuera-Cabeza, Marta Talaverón-Rey, Alejandra Suárez-Carrillo, Ana Romero-González, Jose Antonio Sánchez-Alcázar.

  Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function. In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.

Keywords:  ageing; mitochondria; mitochondrial biogenesis; mitochondrial diseases; mitochondrial dynamics; mitochondrial quality control mechanisms; mitochondrial unfolded protein response (mtUPR); mitophagy; neurodegenerative diseases; therapeutic target

DOI:  https://doi.org/10.3390/biom13121789