bims-proned 2026-05-24 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–05–24
ten papers selected by
Verena Kohler, Umeå University

Fragmentation-Induced Disassembly and Reaggregation of α-Synuclein Amyloid Fibrils.
TDP-43: a critical amplifier of Alzheimer's disease beyond amyloid and tau.
α-Synuclein as a molecular link between Parkinson's disease and chronic kidney disease: insights into the kidney-brain axis.
Kinetics and Spatial Distribution of β-Sheet Development in TDP-43CTD Condensate Maturation.
Role of Lysosomal Genes for Parkinson's Pathogenesis: Insights from Molecular Mechanism to Therapeutic Strategies.
The Influence of Gut Microbiome on Alpha-Synuclein Aggregation: Implications for Parkinson's Disease Pathogenesis.
Precision Medicine in Neurodegenerative Diseases: Genomic Approaches to Target Amyloid-β, Tau, and Alpha-Synuclein Pathways.
Spatial transcriptomics links hippocampal synaptic remodeling to microglial phagocytosis in synucleinopathy.
When copper turns killer: Decoding copper dyshomeostasis and cuproptosis in neurodegenerative pathogenesis and precision metal interventions.
Nanoscale insights into the structure and properties of tau protein fibrils revealed by scanning probe microscopy-based approaches: A review.

ACS Chem Neurosci. 2026 May 20.

Fragmentation-Induced Disassembly and Reaggregation of α-Synuclein Amyloid Fibrils.

Fritjof Havemeister, Vesa Halipi, Marziyeh Ghaeidamini, Elin K Esbjörner.

  Aggregation of the protein α-synuclein (α-syn) is a defining pathological characteristic of Parkinson's disease (PD). Kinetic studies have provided increasingly detailed insights into the mechanisms of α-syn aggregation, highlighting the contributions of secondary nucleation and elongation to fibril growth. However, the understanding of the role of fibril breakage (fragmentation) remains sparse. We therefore established a modified thioflavin-T (ThT) kinetic assay in which ultrasonication steps were introduced when the conversion of α-syn monomers into amyloid fibrils had reached the plateau. This triggered, expectedly, fibril fragmentation but also rapid partial dissociation of the α-syn fibrils and subsequent elongation-dominated fibril regrowth, the kinetics of which could be monitored by ThT and were found to proceed until steady state was reestablished. Interestingly, the regrowth of α-syn variants A30P, E46K, and A53T, but not wild type or variant H50Q, resulted in significant increases in ThT fluorescence even though the residual monomer concentration at steady state was unaffected and no new monomers were added to the assayed systems. Furthermore, for these variants, which are all associated with early-onset PD, the residual monomer concentration was consistently higher than for wild-type α-syn and the late-onset variant H50Q, suggesting differences in monomer-fibril equilibria. Altogether, our study shows that α-syn amyloid fibrils are capable of undergoing structural evolution of a type that alters their ThT binding, highlights the role of fragmentation in expediating such maturation processes, and points out a putative connection between propensity of structural conversion, decreased fibril stability, and early onset of Parkinson's disease.

Keywords:  amyloid kinetics; fibril morphology; fibril stability; fragmentation; polymorphism; thioflavin-T; α-synuclein

DOI:  https://doi.org/10.1021/acschemneuro.5c00895
Neuroscience. 2026 May 20. pii: S0306-4522(26)00341-6. [Epub ahead of print]

TDP-43: a critical amplifier of Alzheimer's disease beyond amyloid and tau.

Abhideep Roy, Sushila Chhetry, Hiramoni Deka, Rubina Roy, Pallab Bhattacharya, Basant Kumar Patel, Anupom Borah.

  TAR DNA-binding protein 43 (TDP-43) proteinopathy has recently emerged as a pivotal, yet underrecognized, contributor to the multifaceted neuropathology of Alzheimer's disease (AD). While amyloid-β and tau have long been established as cardinal pathological hallmarks, growing evidence delineates TDP-43 as a critical participant of neurodegeneration, intricately interwoven with amyloid and tau pathologies. TDP-43 mislocalization, post-translational modifications, and aggregation potentiate neuronal loss through disruption of RNA metabolism, nucleocytoplasmic transport, and protein homeostasis. This tripartite interplay manifests in synergistic and possibly multidirectional pathological cascades that amplify neuronal vulnerability and cognitive decline, thereby complicating the clinical and pathological complexity of AD. Here, we critically reviewed the mechanistic crosstalk among TDP-43, amyloid-β, and tau, focusing on preclinical and clinical evidence, highlighting possible convergent pathways of aggregation, propagation, and neurodegeneration. Moreover, this review also evaluates mitochondrial dysfunction, autophagy failure, and inflammation as underlying events associated with TDP-43 pathology. Therefore, we argue for a reconceptualization of AD as a dynamic proteinopathy network, with TDP-43 as a core integrative node influencing disease onset and its progression. Notably, we discuss emerging diagnostic modalities associated with molecular tracers of TDP-43, providing prospects for future biomarker identification. Finally, this review articulates the translational relevance of TDP-43 therapy in AD and related neurological disorders, emphasizing the necessity of holistic approaches that transcend the traditional amyloid-tau paradigm to effectively tackle the full spectrum of AD pathobiology.

Keywords:  Amyloid beta; Autophagy; Inflammation; Mitochondrial dysfunction; Protein Aggregates; Tau

DOI:  https://doi.org/10.1016/j.neuroscience.2026.05.024
Metab Brain Dis. 2026 May 19. pii: 106. [Epub ahead of print]41(1):

α-Synuclein as a molecular link between Parkinson's disease and chronic kidney disease: insights into the kidney-brain axis.

Shavinder Kumari, Nishant Goutam, Vaishali Chaudhary, Shakshi Rana, Shiv Kumar Kushawaha, Alka Sharma, Mahendra Singh Ashawat, Gaurav Joshi, Neeraj Joshi.

  α-synuclein (α-syn), a presynaptic protein encoded by the SNCA gene, is implicated in the pathogenesis of Parkinson's disease (PD) because of its tendency to misfold and form aggregates. Emerging evidence suggests that α-syn dysfunction may also affect peripheral organs, with chronic kidney disease (CKD) increasingly recognized as a potential comorbidity. This review critically examines current evidence on the molecular pathways linking PD and CKD through α-syn. α-Syn comprises an N-terminal lipid-binding domain, a non-amyloid component (NAC) region prone to aggregation, and a C-terminal domain that regulates conformational stability. Among the proposed mechanisms, mitochondrial dysfunction, oxidative stress, and impaired autophagy-lysosomal clearance represent the most consistently reported pathways across neuronal and renal systems, while activation of the renin-angiotensin system (RAS) has been implicated in more limited or context-dependent studies. Preclinical and limited clinical observations indicate that α-syn-associated processes may contribute to podocyte injury and fibrotic remodeling in renal tissue, whereas reduced α-syn expression has been suggested to compromise epithelial cell stability. These findings support the concept of a kidney-brain axis; however, the extent and directionality of this interaction remain incompletely defined. Novel α-syn-targeted therapies, including ENT-01, Cu(II)ATSM, ambroxol, and lipid-modulating strategies, are being investigated for their cross-organ efficacy, although most evidence currently derives from preclinical or early-phase studies. Importantly, key knowledge gaps persist, including the mechanisms underlying peripheral α-syn aggregation, the pathways of inter-organ communication, and the clinical validity of α-syn-based biomarkers. Overall, current evidence supports a potential role for α-syn as a contributing molecular link between neurodegenerative and renal dysfunction, rather than a definitive unifying mechanism, underscoring the need for integrated and evidence-driven diagnostic and therapeutic approaches.

Keywords:  CKD; Mitochondrial dysfunction; Neurodegeneration; Oxidative stress; PD; Proteostasis; Renal fibrosis; Renin-angiotensin system; α-syn

DOI:  https://doi.org/10.1007/s11011-026-01864-2
ACS Chem Neurosci. 2026 May 22.

Kinetics and Spatial Distribution of β-Sheet Development in TDP-43CTD Condensate Maturation.

Sashary Ramos, Matthew D Watson, Jennifer C Lee.

  Cytosolic inclusions of aggregated TAR DNA-binding protein 43 (TDP-43) are hallmarks of neurodegenerative disorders such as amyotrophic lateral sclerosis and frontotemporal lobar dementia. A prevailing hypothesis suggests that TDP-43 condensates undergo a liquid-to-solid transition during maturation, involving the formation of β-sheet-rich, amyloid-like aggregates. To test this hypothesis, we sought to study the temporal and spatial evolution of protein secondary structure within individual condensates by Raman spectroscopy. We measured in vitro β-sheet development of the C-terminal domain of TDP-43 (TDP-43CTD) at the single-condensate level under physiological solution conditions. All condensates showed apparent single-exponential kinetics (k = 1.6 × 10-5 s-1) for the disordered-to-β-sheet transformation, as indicated by increased amide-I intensity and a shift of the amide-III band to lower energy. Interestingly, the water bend-libration band exhibited a slower rate (k = 4.0 × 10-6 s-1), suggesting that changes in the water environment lag behind protein conformational rearrangement. Further, Raman maps revealed that protein density is highest near the condensate center, whereas β-sheet content is mostly uniform in the interior of the condensate. The unexpected difference between the spatial distributions of β-sheet content and protein density challenges the typical concentration-dependent model of protein aggregation. Importantly, rare events were captured where condensates exhibited spatially asymmetric β-sheet development, revealing localized structural heterogeneity not detectable by ensemble measurements. Collectively, these results provide insight into the temporal and spatial dynamics of protein structure within TDP-43CTD condensates and demonstrate the utility of Raman spectral imaging for tracking condensate maturation.

Keywords:  Raman microspectroscopy; amide-I; amide-III; amyotrophic lateral sclerosis; bend-libration; phase separation; secondary structure

DOI:  https://doi.org/10.1021/acschemneuro.6c00226
Curr Rev Clin Exp Pharmacol. 2026 May 11.

Role of Lysosomal Genes for Parkinson's Pathogenesis: Insights from Molecular Mechanism to Therapeutic Strategies.

Vidhan Chand Bala, Asheesh Kumar Gupta, Amit Kumar, Mukesh Kumar Singh, Arvind Kumar Patel, Sunil Kumar Tiwari, Sushil Kumar.

  Current review aims to clarify the role of lysosomal genes in the pathogenesis of Parkinson's Disease (PD), directing on the molecular mechanisms underlying lysosomal dysfunction and its involvement to α-synuclein accumulation. To deliberates PD-related genes including GBA1, LRRK2, VPS35, PRKN, PINK1, TMEM175, ATP13A2, ATP10B, and DJ1, highlighting their contribution in lysosomal damage. It investigates the disorder of lysosomal enzymes such as cathepsins, glucocerebrosidase, galactocerebrosidase, and acid sphingomyelinase, and the consequent impairment of the autophagic-lysosomal pathway, which helps pathological α-synuclein accumulation. Therapeutic approaches targeting lysosomal dysfunction and α-synuclein pathology are reviewed, including pharmacological chaperones, immunization strategies, enzyme replacement therapies, and small-molecule oligomer modulators. While recent clinical trials expose certain limitations, combinatorial treatment strategies show potential to improve therapeutic efficacy. Lysosomal pathways are critical contributors to PD pathogenesis and denote promising targets for intervention. Integrating mechanistic understandings with developing therapies underlines the importance of targeting lysosomal dysfunction to mitigate α-synuclein aggregation and advance PD treatment.

Keywords:  Parkinson's disease; active immunization; enzyme replacement therapies; lysosomal dysfunction; passive immunization.; pharmacological chaperones; α-synuclein

DOI:  https://doi.org/10.2174/0127724328441801260406095625
Mol Neurobiol. 2026 May 19. pii: 639. [Epub ahead of print]63(1):

The Influence of Gut Microbiome on Alpha-Synuclein Aggregation: Implications for Parkinson's Disease Pathogenesis.

Muskan Sain, Shital Rani, Suraj Pratap Singh, Pritiman Pothal, Shubham Yadav, Ashish Suttee, Akhilesh Kumar, Santosh Kumar, Pavitra Ranawat, Gurpal Singh, Ravi Pratap Barnwal.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder traditionally characterized by dopaminergic neuronal loss in the substantia nigra and the accumulation of misfolded α-synuclein (α-syn) aggregates. While genetic susceptibility and environmental exposures are well-recognized contributors to PD, growing evidence indicates that disease initiation and progression may also involve peripheral mechanisms originating in the gastrointestinal (GI) tract. Early non-motor symptoms such as constipation, along with the presence of α-syn pathology in the enteric nervous system, have led to increasing interest in the gut-brain axis as a critical modulator of PD pathogenesis. Recent literatures reveal that gut microbiota dysbiosis can influence neurodegeneration through immune activation, intestinal barrier dysfunction, and altered production of microbial metabolites, including short-chain fatty acids, bile acids, lipopolysaccharides, and tryptophan-derived compounds. However, the precise molecular mechanisms by which these microbial factors modulate α-syn aggregation, propagation, and clearance remain incompletely understood. In this article, we review current clinical and experimental literature linking gut microbiota alterations to α-syn pathology, with particular emphasis on inflammatory signaling, microbial metabolites, and impaired proteostatic pathways that promote α-syn misfolding. We further integrate emerging concepts of "body-first" and "brain-first" PD subtypes and discuss proposed routes of α-syn transmission from the enteric to the central nervous system, including vagal, hematogenous, and immune-mediated pathways. By highlighting underexplored mechanistic connections between gut dysbiosis and α-syn biology, this review underscores the potential of microbiome-targeted strategies for early diagnosis and disease modification. A deeper understanding of gut-brain communication may ultimately enable personalized therapeutic approaches and reshape current paradigms of PD pathogenesis.

Keywords:  Alpha-synuclein; Gut microbiome; Metagenomics; Microbiota dysbiosis; Neuroinflammation; Parkinson’s disease; Probiotics

DOI:  https://doi.org/10.1007/s12035-026-05917-6
Curr Genomics. 2025 ;26(6): 469-494

Precision Medicine in Neurodegenerative Diseases: Genomic Approaches to Target Amyloid-β, Tau, and Alpha-Synuclein Pathways.

Zaid Waqar, Pranshul Sethi, Divya Jain, Kuldeep Singh, Omar Awad Alsaidan, Sami I Alzarea, Jeetendra Kumar Gupta, Swati Saxena, Mukesh Chandra Sharma.

  Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are characterized by the pathological aggregation of proteins such as amyloid-β, tau, and alpha-synuclein. These hallmark proteins play central roles in disease progression and represent promising targets for therapeutic intervention. Advances in precision medicine, driven by genomic technologies such as CRISPR-Cas systems, RNA-based therapies, and high-throughput sequencing, have enabled the development of tailored strategies to modulate these pathological pathways. This review examines the integration of genomic approaches in targeting amyloid-β, tau, and alpha-synuclein, emphasizing their potential to mitigate disease progression and improve patient outcomes. We highlight current progress in preclinical and clinical studies, discuss challenges associated with translating these therapies into clinical practice, and explore future directions for achieving therapeutic precision in neurodegenerative disorders. By examining the interplay of genetic, molecular, and therapeutic innovations, this review underscores the transformative potential of genomic medicine in addressing the unmet needs of neurodegenerative disease treatment.

Keywords:  CRISPR-Cas; Precision medicine; alpha-synuclein; amyloid-β; genomic therapies; neurodegenerative diseases; tau

DOI:  https://doi.org/10.2174/0113892029372437251010114053
J Adv Res. 2026 May 21. pii: S2090-1232(26)00420-0. [Epub ahead of print]

Spatial transcriptomics links hippocampal synaptic remodeling to microglial phagocytosis in synucleinopathy.

Min-Tae Jeon, Jisu Jeong, Moonseok Choi, Suhyeon Son, Wonjin Yang, Mookyung Cheon, Do-Geun Kim.

   INTRODUCTION: Synucleinopathies, including Parkinson's disease (PD) and Lewy body dementia (LBD), are characterized by misfolding and aggregation of α-synuclein (α-syn) into Lewy bodies, a key pathological hallmark. These disorders display region-specific vulnerability, with PD affecting the nigrostriatal dopaminergic system and LBD involving the neocortex. However, the molecular basis of selective vulnerability, particularly hippocampal involvement, remains poorly understood.
OBJECTIVES: We aimed to determine whether the G2-3 α-synuclein transgenic mouse model recapitulates region-specific vulnerabilities observed in human synucleinopathies and to identify molecular and cellular mechanisms underlying region-specific pathology.
METHODS: Six-month-old G2-3 mice and wild-type (WT) littermates underwent spatial transcriptomics profiling, followed by Gene Ontology (GO) and KEGG enrichment analyses. Key findings were validated using immunohistochemistry and cell-type deconvolution.
RESULTS: Spatial transcriptomics revealed region-specific transcriptomic alterations in the G2-3 synucleinopathy mouse brain, with the hippocampus-particularly the DG and CA subfields-showing the most pronounced changes. GO analysis highlighted enrichment of synapse-related processes, and immunohistochemistry confirmed reduced and mislocalized PSD95 with glial colocalization. KEGG analysis further identified MAPK signaling activation, validated by increased neuronal p-ERK, underscoring hippocampus-specific molecular and structural vulnerabilities under α-syn pathology.
CONCLUSION: Our study demonstrates that the hippocampus is a selectively vulnerable region in the G2-3 synucleinopathy mouse model, showing both transcriptional and structural synaptic alterations. Spatial transcriptomics revealed hippocampal enrichment of synapse-related processes and MAPK signaling, which were corroborated by immunohistochemical evidence of PSD95 mislocalization and neuronal p-ERK activation. These results provide mechanistic insights into hippocampal vulnerability and highlight spatial transcriptomics as a powerful tool to uncover region-specific disease mechanisms in synucleinopathies.

Keywords:  Microglial phagocytosis; Spatial transcriptomics; Synapse organization; Synucleinopathy

DOI:  https://doi.org/10.1016/j.jare.2026.05.025
Neural Regen Res. 2026 Sep 01. 21(9): 3964-3976

When copper turns killer: Decoding copper dyshomeostasis and cuproptosis in neurodegenerative pathogenesis and precision metal interventions.

Wei Du, Tingyao Wu, Yonggang Fan, Min Zhao.

  Copper is an essential cofactor for neuronal metabolism, enzymatic functions, and neurotransmission. However, copper dyshomeostasis-induced redox activity makes the brain vulnerable to oxidative and proteostatic stress. Cuproptosis, a recently characterized form of programmed cell death, is triggered by copper binding to lipoylated enzymes of the tricarboxylic acid cycle, resulting in proteotoxic stress, mitochondrial dysfunction, and cell death. Given that mitochondria are central to copper handling and the primary site of cuproptosis, we examine mitochondrial pathways and key cuproptosis-related genes. We also assess disease-specific signatures of copper imbalance. In Alzheimer's disease, excess copper binds to amyloid-β, promoting aggregation and neurotoxicity. In Parkinson's disease, copper-bound α-synuclein fosters aggregation, while copper-driven redox cycling elevates reactive oxygen species. Cuproptosis worsens mitochondrial vulnerability in Parkinson's disease and impairs cellular stress responses in Huntington's disease. In amyotrophic lateral sclerosis, superoxide dismutase 1-related defects compromise antioxidant defenses alongside copper-dependent mitochondrial dysfunction. In prion diseases, copper facilitates prion protein misfolding and toxicity. Across these disorders, common features include mitochondrial dysfunction and cuproptosis hallmarks-such as enhanced protein lipoylation, elevated reactive oxygen species, impaired electron transport chain activity, fragile Fe-S clusters, and increased reliance on the tricarboxylic acid cycle-which collectively increase neuronal susceptibility to copper dyshomeostasis. Clarifying and understanding the critical roles of copper metabolism not only elucidates the pathogenesis of neurodegenerative diseases but also offers alternative therapeutic strategies. This review uniquely integrates the mitochondria-centered cuproptosis axis with copper dyshomeostasis across Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases, mapping convergent vulnerabilities to mechanism-grounded interventions and outlining testable translational routes.

Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; copper homeostasis; cuproptosis; mitochondrial dysfunction; neurodegenerative disease; prion diseases

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00808
Int J Biol Macromol. 2026 May 21. pii: S0141-8130(26)02575-4. [Epub ahead of print] 152648

Nanoscale insights into the structure and properties of tau protein fibrils revealed by scanning probe microscopy-based approaches: A review.

Kamila Sofińska.

  Tau protein aggregation underlies a spectrum of neurodegenerative disorders collectively known as tauopathies, which manifest through a broad range of clinical symptoms, including motor and behavioral abnormalities, cognitive decline, and age-related memory impairment. Despite decades of research, effective disease-modifying therapies remain elusive. Detailed nanoscale investigations of individual tau aggregates are therefore essential to elucidate the structural heterogeneity that may underlie distinct pathological mechanisms and clinical phenotypes. This review summarizes current knowledge on the structure and morphology of fibrillar tau species at the level of individual filaments. Particular attention is given to the structural diversity of fibrillar tau assemblies, as well as to nanoscale insights into the inhibition of tau assemblies and interactions of tau. The review covers the advances in nanoscale research employing scanning probe microscopy (SPM)-based techniques, including atomic force microscopy (AFM), tip-enhanced Raman spectroscopy (TERS), and infrared nanospectroscopy (AFM-IR). By integrating structural and morphological information at the nanoscale, this review aims to outline emerging directions for understanding the heterogeneity within tau assemblies underlying tau-driven neurodegeneration.

Keywords:  Aggregation; Atomic force microscopy; Fibril; Nanospectroscopy; Spectroscopy; Structure; Tau protein fibrils

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152648