bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2026–06–14
fourteen papers selected by
Verena Kohler, Umeå University
  1. Early Amyloid Formation and Neuroinflammatory Response in a Bigenic Mouse Model Expressing Human α-Synuclein and Aβ.
  2. Alpha-synuclein fibrils induce budding of mitochondrial-derived vesicles.
  3. Dimerization of natively folded molecules drives misfolding and aggregation in Cys-depleted variants of cataract-associated human lens γD-crystallin.
  4. Toward common treatment strategies: convergent proteinopathies and mitochondrial dysfunction in Alzheimer's and Parkinson's diseases.
  5. Glutamate and glutamine metabolism in neurodegenerative diseases.
  6. Inhibitory effect of silymarin on amyloid formation in ALS-associated hSOD1 P66R mutant.
  7. N-terminal acetylation reduces synuclein pathology in models of Parkinson's disease.
  8. Structures and Dynamics of Tau Assemblies from Solid-State NMR.
  9. Human J-domain proteins promote stress granule disassembly and suppress neurodegeneration-linked protein aggregation.
  10. From anti-fungal to potential neurotherapeutic: Posaconazole as an effective inhibitor of cellular TDP-43 pathology.
  11. Propagation of α-synuclein pathology: models, mechanisms and future goals.
  12. Targeting α-Synuclein Aggregation in Parkinson's Disease: A Narrative Review of Current Gene Therapy Strategies.
  13. Aβ Aggregates Bind the U1 Spliceosomal Ribonucleoprotein in Alzheimer Disease Brain.
  14. α-Alkylated α-amino acids reduce the aggregation of unfolded peptides.
  1. Parkinsons Dis. 2026 ;2026 7303965
    Early Amyloid Formation and Neuroinflammatory Response in a Bigenic Mouse Model Expressing Human α-Synuclein and Aβ.
    Radhika Thakore, Markus Aldén, Nadja Gustavsson, Lukas Danielson, Lívia Lins, Jorge Domínguez Sánchez, Ana Rosenthal Arensburg, Agnes Paulus, Iran Augusto Neves da Silva, Valeriia Skoryk, Rakez Kayed, Gunnar K Gouras, Tomas Deierborg, Andreas Heuer, Sabine C Konings, Oxana Klementieva.
      Protein aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and dementia with Lewy bodies. A common feature of these disorders is the misfolding and aggregation of α-synuclein (α-syn) and amyloid-β (Aβ) proteins into amyloid structures, which disrupt cellular homoeostasis and drive disease progression. While Aβ typically forms extracellular deposits and α-syn accumulates in intracellular inclusions, both ultimately contribute to neuronal damage and neurodegeneration. Increasing in vitro evidence suggests that these proteins can interact, altering their structural properties and, in turn, their biological effects; however, the consequences of their co-occurrence in vivo remain unclear. To address this gap, we examined whether α-syn modulates Aβ deposition and associated neuroinflammation at early stages using a physiologically relevant bigenic mouse model coexpressing human α-syn and APP knock-in Aβ. Using combined histological and biochemical analysis, we characterised Aβ load and microglial responses at early time points. Our results indicate that α-syn expression is associated with altered early Aβ deposition and microglial morphology in vivo. Specifically, while early Aβ deposits were detected in both Aβ/α-syn and Aβ-control mice from 2 months of age, at 4 and 6 months, reduced number and size of Aβ microdeposits was observed in the Aβ/α-syn model. The reduction in Aβ load was accompanied by a more ramified microglial morphology consistent with a less activated microglial state. Whether this delayed response reflects protection or impaired immune surveillance remains unclear. Our findings highlight the complexity of indirect Aβ and α-syn interactions and the need for further studies to clarify their functional impact. The newly generated bigenic mice provide a relevant platform to investigate early co-pathology and its role in disease progression.
    Keywords:  amyloid microdeposition; amyloid-βpeptides; microglia; α-synuclein
    DOI:  https://doi.org/10.1155/padi/7303965
  2. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2604082123
    Alpha-synuclein fibrils induce budding of mitochondrial-derived vesicles.
    Thomas Braun, Viviane Reber, Cinzia Tiberi, Andri Fränkl, Dhiman Ghosh, Roland Riek, Tetiana Serdiuk.
      α-synuclein (α-syn) aggregation is a hallmark of synucleinopathies, a class of neurodegenerative disorders such as Parkinson's disease (PD). Several lines of evidence indicate the involvement of mitochondria in the disease pathology. Despite extensive study, the link between α-syn aggregation and mechanisms of mitochondrial toxicity remains not fully understood. Using high-resolution imaging with electron microscopy, we examined SH-SY5Y cells exposed to α-syn fibrils vs control cells with a focus on mitochondria. We found that upon exposure to α-syn fibrils, mitochondria cristae structure gets defects, and mitochondria enhance the budding of mitochondrial-derived vesicles (MDVs). MDV formation reflects an evolutionarily conserved mechanism reminiscent of bacterial outer membrane vesicle biogenesis. Structural proteomics analysis by mass spectrometry corroborates this microscopy observation by identifying changes in multiple proteins that regulate cristae structure, MDV formation, and trafficking. Our results suggest that α-syn may promote MDV generation, and support an important link between α-syn and mitochondria which will be important for future mechanistic studies. The processes we detected could be of interest for diagnostics and potential therapeutic interventions.
    DOI:  https://doi.org/10.1073/pnas.2604082123
  3. J Biol Chem. 2026 Jun 09. pii: S0021-9258(26)02113-7. [Epub ahead of print] 113241
    Dimerization of natively folded molecules drives misfolding and aggregation in Cys-depleted variants of cataract-associated human lens γD-crystallin.
    Yu Pu, Vanie Seecharan, Loy Hashimoto, Aslam Uddin, Eugene Serebryany.
      Cataract, the leading cause of blindness worldwide, results from age-related misfolding and aggregation of long-lived crystallin proteins in the eye lens. The cytoplasm of fiber cells in the lens core becomes increasingly oxidizing with age, allowing non-native disulfides to drive light-scattering aggregation of γ-crystallins. Despite this vulnerability to non-native disulfides, and despite lacking any native-state disulfides, γ-crystallins are unexpectedly Cys-rich. To understand this paradox, we investigated how replacing all four Cys residues in the aggregation-prone N-terminal domain of γD-crystallin affects its stability and aggregation. Cys removal precludes the disulfide-driven aggregation pathway we reported previously. Here, we characterize two full-length human γD-crystallin variants: C18S/C32S/C41S/C78S ("NCS") and C18T/C32A/C41A/C78A ("NCA/T"). Thermodynamic and kinetic stability measurements indicate the N-terminal domain was greatly destabilized in both variants relative to WT, with NCS more destabilized than NCA/T. Upon mild heating or partial denaturation, both variants formed light-scattering aggregates, which were amorphous by transmission electron microscopy. Surprisingly, the aggregation proceeded exclusively from a dimer of natively folded molecules held together by a C-terminal disulfide bridge. These dimers form readily even in the WT protein, and evidence of them has been found in the lens. Aggregation was strongly suppressed by the lens's native chemical chaperone, myo-inositol. The aggregation rate depended linearly on protein concentration, indicating that the rate limiting step was a transformation of the natively-folded to misfolded molecules within the dimer. We propose that many age-related chemical modifications could destabilize the native fold of human γD-crystallin, favor misfolding within disulfide-bridged dimers, and thereby cause aggregation.
    Keywords:  cataract; crystallin; dimerization; disulfide; lens; protein aggregation; protein misfolding; protein stability
    DOI:  https://doi.org/10.1016/j.jbc.2026.113241
  4. Front Neurosci. 2026 ;20 1846384
    Toward common treatment strategies: convergent proteinopathies and mitochondrial dysfunction in Alzheimer's and Parkinson's diseases.
    Julie E V Offerdahl, Danielle E Mor.
      Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent neurodegenerative disorders (ND) globally, disproportionately affecting the elderly population. Traditionally viewed as distinct diseases, AD is defined by symptoms of cognitive impairment and dementia with amyloid-β and tau protein pathologies, while PD is defined by motor symptoms and eventual dementia with α-synuclein (α-syn) protein pathology. However, these pathologies are not unique to either disease, with a large fraction of AD patients displaying α-syn inclusions and PD patients displaying abnormal tau. Emerging evidence indicates that pathological tau and α-syn not only frequently coexist in AD and PD, but may engage in synergistic interactions that promote mitochondrial dysfunction, accelerate neurodegeneration, and worsen cognitive decline in both disorders. This review aims to provide both the prevailing views of AD and PD, as well as a detailed discussion of their commonalities with a focus on how tau and α-syn toxicities intersect at the mitochondrial level. Common features of mitochondrial impairment in AD and PD are discussed, including complex I deficiency, oxidative stress, impaired axonal transport, altered mitochondrial dynamics, and mitochondrial DNA damage. While prior reviews have often examined AD and PD independently, this review specifically focuses on the convergent and potentially synergistic interactions between tau and α-syn at the level of mitochondrial dysfunction, highlighting a shared mechanistic framework that may inform unified therapeutic strategies. By studying and understanding the mutual mechanisms underlying neurodegeneration in AD and PD, common treatment strategies can be identified.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; mitochondria; tau; α-synuclein
    DOI:  https://doi.org/10.3389/fnins.2026.1846384
  5. Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00008-5. [Epub ahead of print]186 1-24
    Glutamate and glutamine metabolism in neurodegenerative diseases.
    Kesharthini Karthikeyan, Gowshika Velmurugan, Riddhi Upadhyay, Murugan Sevanan, Subashchandrabose Chinnathambi.
      Glutamate is known as the most important excitatory neurotransmitter in brain. Glutamate and glutamine recycling is very essential to maintain the nitrogen metabolism. Despite of its major functions, its dysregulation is a basic pathology which is common to neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic lateral sclerosis (ALS). Amyloid-β and Tau in AD disrupt glutamate uptake and the glutamate-glutamine cycle, accelerating synaptic failure, whereas loss of astrocytic EAAT2 in ALS generates unrelenting excitotoxicity and motor neuron demise. Toxic α-synuclein aggregation in PD exacerbates dopamine-glutamate imbalance through destabilizing corticostriatal transmission. This review explores on the key mechanisms by which glutamate impairment leads to the pathogenies of neurogenerative disorders and also about current medications like amantadine, memantine, and riluzole which are glutamate antagonists, are shown to partially alleviative but cannot halt the advancement of the disease. One of the potential targets for disease-modifying treatments could be the receptor modulation, astrocytic function, and elimination of excess glutamate.
    Keywords:  EAAT2 dysfunction; Excitotoxicity; Glutamate dysregulation; Glutamine; VGLUT
    DOI:  https://doi.org/10.1016/bs.irn.2026.01.008
  6. Int J Biol Macromol. 2026 Jun 05. pii: S0141-8130(26)02849-7. [Epub ahead of print]370 152922
    Inhibitory effect of silymarin on amyloid formation in ALS-associated hSOD1 P66R mutant.
    Zahra Hosseinpoor, Bagher Seyedalipour, Nasrin Keivan Behjou, Saman Hosseinkhani, Payam Baziyar.
      The aberrant aggregation of human superoxide dismutase 1 (hSOD1) into β-sheet-rich amyloid fibrils is a crucial process in the pathogenesis of amyotrophic lateral sclerosis (ALS), enhancing motor neuron degeneration and disease progression. The P66R mutation in SOD1 destabilizes local structure and promotes β-sheet-driven fibrillation, which makes it a suitable model for exploring approaches for reducing pathogenic aggregation. Here, we evaluate silymarin, a polyphenolic compound with known antioxidant and neuroprotective properties, for its potential to inhibit P66R-hSOD1 aggregation. ThT fluorescence and transmission electron microscopy analyses demonstrate a significant decrease in amyloid fibril formation in the presence of silymarin; in addition, FTIR spectroscopy confirms the suppression of β-sheet formation. Fluorescence quenching and ANS binding assays indicate a moderate-affinity binding between silymarin and the mutant protein, along with a reduction in surface hydrophobicity. Hemolysis assays confirm its protective effect against membrane damage induced by aggregates, while molecular docking and dynamic simulations indicate that silymarin stabilizes aggregation-prone areas with hydrogen bonding and hydrophobic interactions, thereby promoting compact conformations and reducing solvent-exposed surfaces. The findings identified silymarin as an effective anti-amyloidogenic agent that reduces β-sheet accumulation and fibril formation while also decreasing cytotoxicity, highlighting its potential as a therapeutic candidate for ALS.
    Keywords:  ALS; Amyloid inhibition; Loop IV; P66R mutation; Protein aggregation; Silymarin
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152922
  7. Neurobiol Dis. 2026 Jun 11. pii: S0969-9961(26)00230-5. [Epub ahead of print] 107485
    N-terminal acetylation reduces synuclein pathology in models of Parkinson's disease.
    Esther Del Cid-Pellitero, Thomas Goiran, Zaid A M Al-Azzawi, Nathan C Karpilovsky, Jace Jones-Tabah, Jonas J Mayo, Frederique Larroquette, Wen Luo, Irina Shlaifer, Yogitha Thattikota, Andrew Bayne, Jean-Francois Trempe, Thomas M Durcan, Edward A Fon.
      α-synuclein protein is a major constituent of pathological intracellular inclusions such as Lewy bodies found in brains of patients with Parkinson's disease and other synucleinopathies. Whereas α-synuclein phosphorylation has been much studied, comparatively less work has been devoted to other post-translational modifications such as acetylation, especially given that N-terminally acetylated α-synuclein is the most abundant endogenous form of the protein in the brain. In this study, using multiple in vitro and in vivo models of Parkinson's disease we sought to understand the pathological consequences of N-terminally acetylated α-synuclein. We found that N-terminal acetylation slowed aggregation of both α-synuclein monomers and pre-formed fibrils in seed amplification assay. Uptake of acetylated pre-formed fibrils into both immortalized cell lines and iPSC-derived dopamine neurons was slowed compared to non-acetylated fibrils. In addition, exposure to acetylated pre-formed fibrils induced less seeding of endogenous α-synuclein, as measured by the accumulation of Serine129-phosphorylated α-synuclein inclusions in both iPSC-derived dopamine neurons and mice brains. Finally, mice injected with N-terminally acetylated α-synuclein pre-formed fibrils survived significantly longer than mice injected with non-acetylated fibrils. Taken together, our study indicates that N-terminal acetylation reduces α-synuclein aggregation, uptake into cells, seeding of endogenous α-synuclein, and toxicity in vivo, suggesting that this prevalent post-translational modification represents a potent, physiologically relevant protective mechanism, which has thus far largely not been taken into consideration in most experimental paradigms of Parkinson's disease and synucleinopathies.
    Keywords:  Aggregation; Alpha-synuclein; N-terminal acetylation; Parkinson's disease; Phosphorylated Synuclein; Uptake
    DOI:  https://doi.org/10.1016/j.nbd.2026.107485
  8. Acc Chem Res. 2026 Jun 12.
    Structures and Dynamics of Tau Assemblies from Solid-State NMR.
    Nadia El Mammeri, Mei Hong.
      ConspectusAggregation of the microtubule-associated protein tau into β-sheet fibrils is a hallmark of many neurodegenerative diseases. Understanding the molecular mechanism of tau aggregation requires elucidating the structure and dynamics of fibrillar tau as the end product of aggregation, membrane-bound tau involved in nucleation and intercellular transmission of the aggregates, and microtubule-bound tau as the physiological state of the protein. Using solid-state NMR spectroscopy, we have obtained detailed information about these tau assemblies. Full-length tau fibrils formed in the presence of heparin adopt homogeneous structures that depend on the number of microtubule-binding repeats and that differ from ex vivo tau fibril structures. Phospho-mimetic mutations allowed heparin-free fibrillization, with mutation of the PHF1 epitope yielding a three-layered rigid core that mimics the fold of four-repeat (4R) tau in tauopathies. This three-layered structure is also adopted by other post-translational modification (PTM) mutants, indicating that tau's PTM code contains redundancy and dominance. In all tau fibrils, the rigid core represents only a fifth of the protein. Truncation of the disordered regions accelerated fibrillization, but the fibril fold is sensitive to temperature, pH, and ionic condition of the environment. In a short tau construct, acidic pH stabilized a flat-ribbon dimer structure, whereas neutral pH stabilized the twisted C-shaped fold of Alzheimer's disease (AD) tau. The reproducible in vitro reconstruction of AD-fold tau opens the path for studying small-molecule binding to AD tau for developing diagnostics and therapeutics. However, seeding experiments indicate that full-length tau adopting the AD fold lacks seeding potency; therefore, the rigid core structure alone does not ensure prion-like propagation of pathological tau. Instead, specific fuzzy coat dynamics may be required for serial amplification of tau aggregates. An essential property to replicate is likely the fuzzy coat dynamics. Solid-state NMR data show that tau dynamics depends on PTMs, and the most dynamic segments in three-layered tau lie in the proline-rich region, suggesting that separation of this region from the rigid core may be important for prion-like propagation of tau aggregates. Cholesterol-rich high-curvature lipid membranes alone induce tau fibrils and allow their insertion into the membrane, supporting the model that lipid membranes are involved in the nucleation and transmission of tau aggregates. Finally, solid-state NMR data show that the highest-affinity microtubule-binding domain of tau is the R' segment that is N-terminal to the PHF1 epitope, suggesting that stabilizing this segment may inhibit aggregation. These solid-state NMR data of multiple types of tau assemblies have provided numerous insights into the structures and dynamics of tau in pathology and physiology, advancing the reconstruction of the aggregation mechanism of tau in neurodegeneration.
    DOI:  https://doi.org/10.1021/acs.accounts.6c00208
  9. Cell Rep. 2026 Jun 08. pii: S2211-1247(26)00404-3. [Epub ahead of print]45(6): 117326
    Human J-domain proteins promote stress granule disassembly and suppress neurodegeneration-linked protein aggregation.
    Giovanni J Mastromarco, Rebecca Earnshaw, Gaelen Moore, X Y Sherwin Xu, Nour H Sadek, Fiona Cui, Natalie Lo, Hyun O Lee.
      Stress granules are conserved biomolecular condensates that form under stress and rapidly disassemble during recovery. Stress granules have been linked to pathological protein aggregation and their impaired disassembly reduces cell viability, yet the mechanisms governing their clearance and protein aggregation remain unclear. We find that human HSP70 and a subset of J-domain proteins (JDPs) localize to stress granules and that chemical or genetic inhibition of these chaperones markedly slows granule disassembly. Conversely, overexpressing these JDPs, particularly DNAJB1, accelerates disassembly without altering assembly. In vitro, HSP70 and DNAJB1 partition into G3BP1 condensates and reduce their size in an ATP-dependent manner. In cells expressing amyotrophic lateral sclerosis (ALS)-linked mutant FUS, DNAJB1 depletion further impairs stress granule clearance and promotes pre-amyloid accumulation, while depleting a non-stress granule JDP has no effect. Our findings demonstrate that specific JDP chaperones enhance stress granule disassembly and help limit aberrant protein aggregation.
    Keywords:  ALS; CP: molecular biology; CP: neuroscience; FUS; HSP70; J-domain proteins/HSP40; biomolecular condensates; cellular stress response; molecular chaperones; neurodegeneration; protein aggregation; stress granules
    DOI:  https://doi.org/10.1016/j.celrep.2026.117326
  10. bioRxiv. 2026 Jun 04. pii: 2026.06.01.728552. [Epub ahead of print]
    From anti-fungal to potential neurotherapeutic: Posaconazole as an effective inhibitor of cellular TDP-43 pathology.
    Noah Nathan Kochen, Sophia Zafari, Aimee Renaud, Nathan Schneider, Nagamani Vunnam, Elly E Liao, James R Dutton, Anthony R Braun, Jonathan N Sachs.
      Recently, we showed that ketoconazole, a known anti-fungal inhibitor of CYP51, stabilized TAR DNA-binding protein 43 (TDP-43) native self-interactions, reduced TDP-43 pathology and rescued TDP-43-induced SREBP2 downregulation. Despite its promising effects, ketoconazole is not viable for repurposing for ALS due to liver toxicity side effects that occur when orally delivered. To address this, we tested the activities of seven additional known azole-based CYP51 inhibitors in order identify a viable alternative to ketoconazole. Using our established TDP-43 mislocalization and aggregation assay in HEK293T cells, we identified posaconazole, an FDA-approved, CNS-penetrant and orally delivered anti-fungal, as the strongest inhibitor of TDP-43 pathology. Posaconazole was able to reduce insoluble TDP-43 and restore SREBP2 levels, outperforming ketoconazole. Mechanism of action (MOA) experiments suggest posaconazole is able to outperform ketoconazole by inducing a significantly stronger activation of autophagy and upregulation of heat shock proteins known to clear TDP-43. Further MOA experiments show that the effects of posaconazole on TDP-43 are dependent on its known ability to lower cellular cholesterol levels. By correlating our experimental results on the eight CYP51 inhibitors tested, we show that predicted affinity towards human CYP51 strongly correlates with the inhibitors' ability to lower TDP-43 aggregation and mislocalization. Finally, we tested posaconazole in a low dose sodium arsenite ALS model in iPSC-derived motor neurons, showing that it is efficacious at inhibiting TDP-43 pathology in the nanomolar range. Altogether, these results support the repurposing of posaconazole for ALS/FTD as a means to prevent TDP-43 pathology.
    DOI:  https://doi.org/10.64898/2026.06.01.728552
  11. Mol Neurodegener Adv. 2026 ;2(1): 26
    Propagation of α-synuclein pathology: models, mechanisms and future goals.
    Aryeh Zolin, Sarah A Weber, Yan Xin Xie, Jacqueline Burré.
      Misfolding and aggregation of α-synuclein underlies several progressive neurodegenerative disorders for which there are no disease-modifying therapies, most notably Parkinson's disease. α-Synuclein pathology can be transmitted across adjacent cells, and this prion-like property is thought to underlie disease progression. Here, we review what is known about how α-synuclein pathology spreads between cells and evaluate the different model systems used to address this question, including cultured cells, invertebrates, rodents, and non-human primates. Cellular systems have revealed potential molecular mechanisms underlying α-synuclein release and uptake. However, they lack the physiological complexity needed to recapitulate circuit-level spread. Invertebrate models overcome this limitation but lack endogenous α-synuclein. Rodents are the most frequently used model and have provided key insights into the anatomical progression of pathology. Inoculation of pathogenic α-synuclein into targeted regions initiates sequential involvement of connected structures, revealing principles such as directionality, selective vulnerability, and synaptic connectivity to pathology propagation. Yet, they incompletely model the slow time course and multisystem involvement seen in patients. Non-human primate models offer a closer representation of human neuroanatomy, synaptic organization, and lifespan. These models capture features such as long-distance propagation, dopaminergic neuron degeneration, and the emergence of motor symptoms over extended periods. Their value lies in bridging molecular mechanisms with organism-level dysfunction, but they face technical and practical limitations. Together, these complementary systems have provided insight into how α-synuclein pathology spreads across the brain. In reviewing the literature, we find there is little consensus and no cogent understanding of the mechanisms underlying release and uptake of pathologic α-synuclein aggregates. We propose a need for a deeper understanding of how α-synuclein aggregation spreads. This requires integrating insights across cellular, rodent, and primate models and leveraging the strengths of each system to enable the identification of targetable mechanisms of transmission and guide the development of disease-modifying therapies.
    Graphical Abstract:
    Keywords:  Models; Parkinson’s disease; Propagation; Seeding; Synucleinopathies; α-Synuclein
    DOI:  https://doi.org/10.1186/s44477-026-00038-9
  12. Curr Neuropharmacol. 2026 Jun 08.
    Targeting α-Synuclein Aggregation in Parkinson's Disease: A Narrative Review of Current Gene Therapy Strategies.
    Kuldeep Singh, Pranshul Sethi, Divya Jain, Jeetendra Kumar Gupta, Arpan Kumar Tripathi, Sarvesh Rustagi, Ajay Guru, Mohammad Tabish, Amin Gasmi.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the accumulation of misfolded α-synuclein (α-syn) aggregates, leading to dopaminergic neuronal loss and motor dysfunction. Current pharmacological treatments primarily provide symptomatic relief and have a limited impact on disease progression. This article presents a narrative review of emerging gene therapy approaches aimed at modulating α-syn expression, aggregation, and clearance as potential disease-modifying strategies for PD. Gene-based interventions include viral vector-mediated gene delivery, antisense oligonucleotides, RNA interference, and gene-editing technologies. Preclinical studies and early-phase clinical trials suggest that these approaches may reduce α-syn burden, improve motor outcomes, and support dopaminergic neuron preservation. Adeno-associated viral and lentiviral vectors have demonstrated promise for targeted central nervous system delivery, although challenges related to dosage optimization, regional specificity, long-term safety, and immune responses remain. Complementary strategies focusing on enhancing molecular chaperone activity and activating autophagy-lysosomal pathways have also shown potential in facilitating α-syn clearance. Despite encouraging progress, several limitations hinder clinical translation, including off-target effects, immune activation, and the need to preserve physiological α-syn functions essential for neuronal homeostasis. Future success will depend on precise molecular targeting, optimized delivery platforms, and rigorous safety evaluation through well-designed clinical trials. This narrative review summarizes current advances, key limitations, and future directions in α-syn-targeted gene therapy, highlighting its potential role in advancing PD treatment beyond symptomatic management toward disease modification.
    Keywords:  Parkinson's disease; alpha-synuclein; gene therapy; neurodegeneration; targeted interventions.
    DOI:  https://doi.org/10.2174/011570159X431647260525102713
  13. bioRxiv. 2026 Jun 05. pii: 2026.06.02.729610. [Epub ahead of print]
    Aβ Aggregates Bind the U1 Spliceosomal Ribonucleoprotein in Alzheimer Disease Brain.
    Youqi Tao, Anna E Francis, Wen Liu, Christopher Watkins, David A Bennett, Dennis J Selkoe, Ryan A Flynn, Andrew M Stern.
      Missplicing due to U1 small nuclear ribonucleoprotein (U1 snRNP) insolubilization and dysfunction has been identified in Alzheimer disease (AD) brain. Cytoplasmic aggregation and mislocalization of the U1 snRNP partly co-localizes with tau neurofibrillary tangles, and some evidence for tau-U1 binding has been identified. However, tau-U1 co-localization by immunohistochemistry is only partial, and insoluble U1 small nuclear RNA (snRNA) binding proteins correlate better with Aβ than with tau in unbiased proteomics. While investigating the sedimentation characteristics of Aβ aggregates capable of diffusing out of AD brain tissue, we unexpectedly found that some were bound to small RNA. Aβ immunoprecipitation and deep sequencing revealed the U1 snRNA, with specific binding confirmed through reverse immunoprecipitation and oligonucleotide hybridization. Double immunoelectron microscopy revealed decoration of Aβ fibrils, more than tau fibrils, with the U1-70k protein, a component of the U1 snRNP. Immunofluorescence of unfixed cryostat sections but not formalin fixed paraffin embedded sections of AD brain revealed labeling of a subset of amyloid plaques with anti-U1-70k antibodies, confirmed by RNA in situ hybridization of the U1 snRNA. We conclude that a subset of AD brain Aβ aggregates are bound to the U1 snRNP at the edges of some amyloid plaques, explaining prior proteomics findings. These data provide a potential link between Aβ aggregation and spliceosome dysfunction and unite Aβ with other fibril-forming proteins across the neurodegenerative diseases whose aggregation is affected by RNA binding.
    DOI:  https://doi.org/10.64898/2026.06.02.729610
  14. RSC Adv. 2026 Jun 02. 16(33): 30200-30204
    α-Alkylated α-amino acids reduce the aggregation of unfolded peptides.
    Haoliang Zheng, Robert W Newberry.
      Aberrant aggregation complicates the development of bioactive peptides. Here, we generate new α-ethylated variants of proteinogenic amino acids and demonstrate that they reduce peptide aggregation through a mechanism distinct from their α-methylated counterparts. Whereas α-methylated residues reduce aggregation by favoring helix formation, α-ethylated residues prevent aggregation without promoting secondary structure.
    DOI:  https://doi.org/10.1039/d6ra03257e
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