bims-proned 2026-08-23 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–08–23
nine papers selected by
Verena Kohler, Umeå University

Protease-Mediated TAR DNA-Binding Protein 43 (TDP-43) Pathogenesis: From Molecular Mechanisms to Therapeutic Opportunities.
Multimerization of a rationally designed nanobody for enhanced avidity toward Aβ42 oligomers.
A Toxic Tau-PFKFB3 Circuit Reduces F2,6BP Levels and Drives Neurodegeneration.
Tau-targeting pharmacological strategies in neurodegenerative disease.
Zinc-finger ubiquitin-binding domain of histone deacetylase 6 modulates Tau structure and function.
Synergetic inhibition of deubiquitinases and acetyltransferases to regulate tau acetylation and aggregation in SH-SY5Y cell line model of Alzheimer's disease.
Neuronal overexpression of Kcnn1 in A53T α-synuclein mice suppresses phospho-serine 129 α-synuclein formation and doubles survival time.
The mitophagy-inflammasome axis: a shared pathological hub in Alzheimer's and Parkinson's diseases.
Protein Homeostasis and Mitochondrial Quality Control in Neurodegeneration.

ACS Pharmacol Transl Sci. 2026 Aug 14. 9(8): 2076-2091

Protease-Mediated TAR DNA-Binding Protein 43 (TDP-43) Pathogenesis: From Molecular Mechanisms to Therapeutic Opportunities.

Joyal Xavier, Meenakshi Singh, Sampada Tamhankar, Kristine Griffett, Rajesh Amin.

  TDP-43 proteinopathy is the defining pathological feature in approximately 50% of frontotemporal lobar degeneration (FTLD) cases, yet the precise mechanism or biochemical transition from nuclear proteostasis to cytoplasmic toxicity remains a critical knowledge gap. While its role in repressing nonconserved cryptic exons is well reported, this review highlights and explores the synergy between site-specific proteolysis and post-translational modification (PTM)-induced phase transitions. We propose a mechanism where primary endoproteolytic cleavage by calpain, caspase, and asparaginyl endopeptidase acts as a "protease switch" to generate a C-terminal fragment that disturbs the nuclear import ability of TDP43. These fragments serve as preferred substrates for coordinated hyperphosphorylation and SUMOylation, which drive widespread transcriptome shutdown. We emphasize that synthesizing a small-molecule bridge between these proteins and TDP-43 reduces aberrant protease-mediated fragmentation and delocalization of many proteins. Therefore, in this review, we highlight several therapeutic drug discovery strategies to intercept TDP-43 at the preaggregation stage and restore its function, offering disease-modifying pathways.

Keywords:  TDP-43 aggregation; frontotemporal dementia; neurodegeneration; proteases

DOI:  https://doi.org/10.1021/acsptsci.6c00171
Protein Sci. 2026 Sep;35(9): e70754

Multimerization of a rationally designed nanobody for enhanced avidity toward Aβ42 oligomers.

Magdalena Nowinska, Elijah Suh, Casey Mogilevsky, Michele Vendruscolo.

  Alzheimer's disease affects tens of millions of people worldwide and is associated with the self-assembly of the Aβ42 peptide into amyloid aggregates. Among the species formed during this process, soluble oligomeric intermediates are the most closely linked to neurotoxicity and are therefore an attractive target for both therapeutic and diagnostic strategies. Their conformational heterogeneity and transient nature, however, have so far hindered the development of reagents that recognize them selectively, and no fully quantitative biomarker of Aβ42 oligomers is widely available. To address this problem, we use a rationally designed conformation-specific single-domain antibody, DesAbO, which binds selectively to Aβ42 oligomers. By using enzyme-linked immunosorbent assay, we show that encoding self-assembling multimerization domains in the DesAbO plasmid yields multimeric variants with increased avidity toward Aβ42 oligomers. In aggregation assays, the multimeric variants inhibited Aβ42 aggregation at concentrations at which the monomeric form was no longer effective, with the SB175 trimer performing best. These results show how multimerization can be used to enhance the recognition of Aβ42 oligomers and offer a route toward diagnostic and therapeutic agents for Alzheimer's disease and other protein misfolding disorders.

Keywords:  Alzheimer’s disease; Aβ42 oligomers; avidity; multivalency; nanobodies; protein aggregation

DOI:  https://doi.org/10.1002/pro.70754
bioRxiv. 2026 May 31. pii: 2026.05.28.728580. [Epub ahead of print]

A Toxic Tau-PFKFB3 Circuit Reduces F2,6BP Levels and Drives Neurodegeneration.

Santi M Mandal, Anirban Chakraborty, Shandy Shahabi, Mikita Mankevich, Adrian Povo-Retana, Tapan Biswas, Sergio Sanchez-Garcia, Sravan G Sreenivasmurthy, Lucia Zhou Yang, Joseph Herdy, Jerome Mertens, Fred H Gage, Johannes Cm Schlachetzki, Balaji Krishnan, Lisardo Bosca, Tapas Hazra, Gourisankar Ghosh.

Alzheimer's disease (AD) and related dementias are progressive neurodegenerative disorders manifested by aggregation of Tau and Amyloid beta (Aβ). Emerging evidence suggests that metabolic dysregulation contributes to AD pathogenesis, yet how metabolic alterations interface with neuronal integrity remains unclear. Here, we identify dysfunction in PFKFB3-F2,6BP (fructose-2,6-bisphosphate) metabolic axis as a key feature of AD. We show that pathological Tau aggregates aberrantly sequester PFKFB3, limiting its activity and resulting in F2,6BP depletion. F2,6BP exerts protective effects through multiple convergent mechanisms: (i) direct activation of polynucleotide kinase 3'-phosphatase (PNKP) to facilitate DNA strand break repair; (ii) transcriptional upregulation of the protein phosphatase 2A catalytic subunit (PP2CA) to limit Tau phosphorylation; (iii) stabilization of PFKFB3 to diminish its sequestration into aggregates; and (iv) direct inhibition of Tau aggregation. These findings establish F2,6BP as a central node linking metabolic regulation to both genomic stability and proteostasis in AD. Importantly, exogenous F2,6BP supplementation rescues multiple pathological features across diverse model systems, including induced neuronal cell lines (iN), primary neurons, organotypic hippocampal slice cultures, and in a Drosophila model of AD. These findings redefine F2,6BP as a metabolite that directly coordinates genome maintenance and proteostasis in neurons. Overall, this study identifies the PFKFB3-F2,6BP axis as a central driver of AD pathogenesis and a promising therapeutic target.
Highlights: Tau aggregates sequester PFKFB3 depletes neuronal F2,6BPF2,6BP links metabolism to DNA repair and Tau proteostasisF2,6BP activates PNKP and upregulates PP2A to counter Tau pathologyF2,6BP supplementation rescues AD phenotypes across models.

DOI: https://doi.org/10.64898/2026.05.28.728580
Trends Pharmacol Sci. 2026 Aug 17. pii: S0165-6147(26)00177-X. [Epub ahead of print]

Tau-targeting pharmacological strategies in neurodegenerative disease.

Hanyuan Zheng, Jie Zheng.

  Pathological tau accumulation underlies a spectrum of neurodegenerative diseases collectively known as tauopathies. Although reducing tau remains the prevailing therapeutic strategy, indiscriminate tau reduction may compromise physiological functions and has demonstrated limited clinical efficacy. Growing evidence indicates disease- and stage-specific tau heterogeneity-spanning post-translational modifications (PTMs), aggregation states, and vulnerable cell populations-highlighting the necessity for improved targeting selectivity for pathological tau species. In this review, we discuss tau-targeting therapeutic modalities, including nucleic acids to suppress tau expression, immunotherapies and chimeric degraders to facilitate tau protein clearance, inhibitors of aggregation, and emerging strategies for tau PTM-editing and cellular-level interventions for neurofibrillary tangle-bearing neurons.

Keywords:  Alzheimer’s disease; cell therapy; targeting chimera; tau; tauopathy

DOI:  https://doi.org/10.1016/j.tips.2026.07.008
Methods Enzymol. 2026 ;pii: S0076-6879(26)00164-3. [Epub ahead of print]733 81-110

Zinc-finger ubiquitin-binding domain of histone deacetylase 6 modulates Tau structure and function.

Abhishek Ankur Balmik, Subashchandrabose Chinnathambi.

  Histone deacetylase 6 (HDAC6), a predominantly cytoplasmic deacetylase, has emerged as a critical regulator of protein homeostasis, and plays an important role in neurodegenerative disorders characterized by Tau pathology. We investigated the role of zinc-finger ubiquitin-binding domain (ZnF UBP) of HDAC6 in modulating tau structure and function. HDAC6 is well known for its deacetylase activity and involvement in aggresome formation but the functional contribution of its ZnF UBP domain in tau biology remains not well explored. Using a combination of biochemical, biophysical, and molecular approaches, we demonstrate that the ZnF UBP domain of HDAC6 directly interacts with tau, influencing its conformational dynamics and aggregation propensity. Our findings reveal that this interaction is independent of HDAC6's catalytic deacetylase activity, highlighting a non-canonical mechanism through which HDAC6 regulates tau. Structural analyses indicate that binding of ZnF UBP induces conformational rearrangements in tau, potentially altering its microtubule-binding capacity and aggregation behavior. Furthermore, we show that the HDAC6-tau interaction modulates tau aggregation, suggesting a protective or regulatory role in preventing aberrant tau aggregation. Functional assays support the notion that ZnF UBP-mediated modulation of tau contributes to maintaining cytoskeletal integrity and cellular proteostasis. These observations suggests that HDAC6 functions not only as a deacetylase but also performs regulatory functions through ZnF UBP domain that can influence the function and properties of intrinsically disordered proteins (IDPs) like tau. Overall, this chapter provides mechanistic insights into the non-enzymatic functions of HDAC6, specifically through its ZnF UBP domain, in regulating tau structure and function. Understanding this interaction expands the current perspective on HDAC6 biology and underscores its potential as a therapeutic target in tauopathies, including Alzheimer's disease and targeting domain-specific interactions of HDAC6 may offer a novel therapeutic strategy to modulate tau pathology.

Keywords:  Alzheimers disease; Histone deacetylase 6; Tau; Zinc-finger ubiquitin-binding domain (ZnF UBP)

DOI:  https://doi.org/10.1016/bs.mie.2026.05.036
Methods Enzymol. 2026 ;pii: S0076-6879(26)00162-X. [Epub ahead of print]733 297-319

Synergetic inhibition of deubiquitinases and acetyltransferases to regulate tau acetylation and aggregation in SH-SY5Y cell line model of Alzheimer's disease.

Basavaraju K C, Harshitha D K, Poornima Priyadarshini.

  Tau protein homeostasis depends on a balance between ubiquitination and acetylation, two key post-translational modifications (PTMs) which simultaneously compete for lysine residues that govern tau stability. Importantly, ubiquitination signals of proteins for degradation through the 26S proteasome, whereas acetylation prevents ubiquitin attachment, leading to tau stabilization and an increased risk of aggregation. In Alzheimer's disease (AD), this balance is disrupted by upregulation of acetyltransferase activity, such as p300/CBP, and increased deubiquitinase (DUBs) activity, which together hinder proteasomal clearance and accumulation of pathological tau. Since these pathways are interconnected, targeting only one may be insufficient to address tau-mediated neurotoxicity. In this book chapter, we highlight the importance of a dual approach aimed at inhibiting both aberrant acetylation and deubiquitinases activity, thereby restoring ubiquitination and promoting tau degradation. In addition, the development of standardized cell culture models in the SH-SY5Y neuronal system will be crucial to evaluating the therapeutic potential of this synergetic inhibition strategy.

Keywords:  26S proteasome; Acetyltransferases; Alzheimer’s disease; Deubiquitinases; EP300; Ubiquitination

DOI:  https://doi.org/10.1016/bs.mie.2026.05.034
Proc Natl Acad Sci U S A. 2026 Aug 25. 123(34): e2622262123

Neuronal overexpression of Kcnn1 in A53T α-synuclein mice suppresses phospho-serine 129 α-synuclein formation and doubles survival time.

Maria Nagy, Wayne A Fenton, Arthur L Horwich.

  Synucleinopathies, including idiopathic Parkinson's Disease, are driven by misfolding and aggregation of the 140 residue α-synuclein protein that plays a role in presynaptic vesicle regulation. We describe effects of a modifier, neuronal overexpression of the mouse calcium-activated potassium channel subunit Kcnn1, on a mouse model in which transgenic Thy1.2-driven human A53T α-synuclein directs fully penetrant lethal motor disease. Kcnn1 overexpression increased median survival of these mice from 8.5 to 18 mo, associated with an altered presentation from rapidly progressive dystonic-like behavior of the limbs to a later-onset (12 to 16 mo) and slowly progressive lower limb clasping when lifted by the tail. At the tissue level, accretion of disease-associated phospho-serine 129 α-synuclein was prevented by overexpression of Thy1.2-driven Kcnn1 in many brain regions/spinal cord, where phospho-serine 129 α-synuclein copiously accreted in A53T mice at endstage. The action of blocking production of phospho-serine 129 α-synuclein was also observed in adult A53T mice injected presymptomatically with an AAV9 scCMV-Kcnn1 virus into the right superior colliculus. At endstage ~2 mo later, the right superior colliculus exhibited overexpression of Kcnn1 and showed essentially no phospho-serine 129 α-synuclein, whereas the uninjected left superior colliculus exhibited copious phospho-serine 129 α-synuclein. The neuroprotective action of Kcnn1 overexpression remains to be fully resolved, but the channel protein subunit, targeted to the ER membrane, has been shown to induce an ER stress response. This response, which may activate autophagy, along with potential channel formation, may diminish the rate of formation or lifetime of neurotoxic forms of A53T α-synuclein.

Keywords:  AAV9; Kcnn1; phosphosynuclein; synucleinopathy; α-synuclein

DOI:  https://doi.org/10.1073/pnas.2622262123
Transl Neurodegener. 2026 Aug 17. pii: 38. [Epub ahead of print]15(1):

The mitophagy-inflammasome axis: a shared pathological hub in Alzheimer's and Parkinson's diseases.

Wei Long, Mengqin Yuan, Sirui Wang, Xinyue Tan, Li-Chen Gao.

  Alzheimer's disease (AD) and Parkinson's disease (PD) represent the most prevalent chronic neurodegenerative disorders, characterized by progressive loss of neurons as a core pathological feature. Despite discrepancies in their clinical phenotypes and signature pathological proteins, accumulating evidence has validated a common molecular pathogenic mechanism: dysfunctional bidirectional crosstalk between mitophagy and inflammasomes. As the central hub of neuronal energy metabolism, mitochondrial impairment triggers the release of damage-associated molecular patterns such as reactive oxygen species and mitochondrial DNA, which in turn activate inflammasomes (e.g., NLRP3) to elicit chronic neuroinflammation. Conversely, excessive inflammasome activation suppresses mitophagy, exacerbating the accumulation of damaged mitochondria and pathological protein aggregates, and forming a pathological mitochondrial damage-inflammatory activation-autophagy inhibition cycle. Microglia and astrocytes, key immunocompetent cells of the central nervous system, act as a hub within this regulatory network. Therapeutic strategies targeting the mitophagy-inflammasome axis have achieved remarkable advancements, including mitophagy agonists, inflammasome inhibitors, and dual-target modulators. This review summarizes recent findings regarding the pathogenic roles of β-amyloid and α-synuclein in AD and PD, as well as the protective effects offered by regulating mitophagy and inflammasome activity. Furthermore, the major directions and potential hurdles in the development of targeted therapeutics are discussed, in the aim of providing insights into the novel therapeutic avenues for the treatment of both disorders.

Keywords:  Inflammasome; Mitophagy; Targeted therapy; α-Synuclein; β-Amyloid

DOI:  https://doi.org/10.1186/s40035-026-00578-w
WIREs Mech Dis. 2026 Jul-Aug;18(4):18(4): e70014

Protein Homeostasis and Mitochondrial Quality Control in Neurodegeneration.

Rosa Di Lorenzo, Rola S Zeidan, Riccardo Calvani, Vito Pesce, Emanuele Marzetti, Anna Picca.

Quality control (QC) processes include a network of cellular pathways that prevent the accumulation of toxic aggregates by repairing, recycling, and/or eliminating defective components, including mitochondria. Among these pathways are the proteostasis network, which regulates the proteome, and mitochondrial quality control (MQC) mechanisms, which maintain mitochondrial number and integrity. QC relies on a hierarchically and spatially integrated regulatory axis rather than individual parallel units. Such systems coordinate mitochondrial biogenesis, dynamics, and autophagic recycling with proteostasis to ensure the maintenance of high-quality mitochondria and bioenergetically efficient cells. Neurons, post-mitotic cells with high energy demands, depend heavily on these mechanisms and on the spatial coordination of MQC. Here, we discuss how failure of this integrated QC axis, rather than dysfunction of its individual components alone, can drive neuronal decline and contribute to the neurodegeneration.

DOI: https://doi.org/10.1002/wsbm.70014