bims-proned 2026-04-05 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–04–05
fourteen papers selected by
Verena Kohler, Umeå University

Small Molecule Inhibitors Targeting Pathogenic Protein Aggregation in Neurodegenerative Diseases: Medicinal Chemistry and Mechanistic Insights.
Cinnamon Bud Extract Is a Source of Biomolecules Active against the Aggregation and Condensation of Alzheimer's-Associated Tau Protein.
Molecular chaperones mediated proteostasis depletion: A cause of neurodegeneration?
Extracellular Protein Quality Control in Tau Pathology.
Decode the Ubiquitinome in Parkinson's Disease: From Pathological Aggregates to Targeted DUB Therapeutics.
UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration.
Transient Interactions of α-Synuclein N- and C-Termini.
Electric Double Layer Phenomena Near Surfaces Irreversibly Trigger Assembly of Tau Protein.
Molecular mechanisms underlying exercise-enhanced autophagy in improving neuroplasticity in Alzheimer's disease.
Tau-Cytoskeleton and their interaction with other neurodegenerative proteins.
Pathological microtubule dynamics in Parkinson's disease: Mechanisms and therapeutic implications.
The quest to restore neuronal structure: Targeting cytoskeletal proteins in neurodegenerative diseases.
Incense Aerosol-Induced Neurotoxicity Disrupts α-Synuclein Homeostasis in a Cellular Parkinson's Disease Model, Distinct from Cigarette Aerosols.
Neuroinflammation, Autophagy, and Neurodegeneration: Mechanisms and Therapeutic Insights.

Curr Top Med Chem. 2026 Apr 01.

Small Molecule Inhibitors Targeting Pathogenic Protein Aggregation in Neurodegenerative Diseases: Medicinal Chemistry and Mechanistic Insights.

Kishna Ram Senwar, Anjali Dhillon, Monu Yadav.

  A hallmark of Neurodegenerative Diseases (NDs) is protein misfolding, aggregation, and accumulation in specific brain regions. The accumulation of insoluble, misfolded protein aggregates is usually referred to as amyloid formation. This process leads to cellular dysfunction, destruction of neurons, loss of neuronal connections in specific brain areas, and brain damage. Despite the involvement of distinct pathogenic proteins, the underlying mechanisms of misfolding and aggregate formation are remarkably similar across various NDs. In this review, we present a comprehensive overview of the medicinal chemistry and mechanistic insights into phytochemicals and synthetic small molecules with potential for the treatment of neurodegenerative disorders. Various small molecules have been reported to have therapeutic effects by inhibiting the misfolding, aggregation, and accumulation of pathogenic proteins, such as amyloid-β, tau, and α- synuclein. This review mainly covers natural product-derived small molecules, notably polyphenols (including flavonoids and non-flavonoid polyphenols), as well as other phytochemical classes, such as quinones and alkaloids, along with their possible mechanisms of action. In addition, synthetic small molecules, osmolytes, metal chelators, and repurposed drugs for neurodegenerative disorders are thoroughly discussed.

Keywords:  Alzheimer’s disease (AD); Amyloid-β (Aβ); Neurodegenerative diseases; Parkinson's disease (PD); polyphenols; small molecule inhibitors; tau protein; α-Synuclein.

DOI:  https://doi.org/10.2174/0115680266439510260223082224
J Agric Food Chem. 2026 Apr 02.

Cinnamon Bud Extract Is a Source of Biomolecules Active against the Aggregation and Condensation of Alzheimer's-Associated Tau Protein.

Giovanna Viola, Andrea Sperotto, Alessandro Palmioli, Roberto Tira, Francesca Munari, Michael Assfalg, Cristina Airoldi, Mariapina D'Onofrio.

  Abnormal accumulation of tau fibrillar aggregates is a hallmark of tauopathies, including Alzheimer's disease. Targeting tau aggregation represents a promising strategy for preventing and treating neurological disorders, especially using natural compounds with favorable safety profiles. In this study, we investigated a hydroalcoholic extract of Cinnamomum cassia buds (BCHE) and its major components, cinnamaldehyde and shikimic acid, for their effects in modulating tau repeat domain aggregation and liquid-liquid phase separation. In vitro results show that BCHE and cinnamaldehyde inhibit tau aggregate maturation, promoting the formation of nonfibrillar, off-pathway species and modulating condensate formation. These alternative aggregates exhibit reduced cytotoxicity in SH-SY5Y neuroblastoma cells and lower seeding capacity than canonical fibrils. BCHE also contains compounds capable of binding preformed tau fibrils. Overall, these findings suggest a novel mechanism by which cinnamon-derived bioactive molecules mitigate tau aggregation and reduce its cellular toxicity, highlighting their potential as neuroprotective agents.

Keywords:  NMR; cinnamaldehyde; cinnamon bud biomolecules; inhibition; liquid–liquid phase separation; protein aggregation; shikimic acid; tau protein; tauopathies

DOI:  https://doi.org/10.1021/acs.jafc.5c17659
Adv Protein Chem Struct Biol. 2026 ;pii: S1876-1623(25)00129-4. [Epub ahead of print]150 181-219

Molecular chaperones mediated proteostasis depletion: A cause of neurodegeneration?

Sumit Kinger, Akash Choudhary, Prashant Kumar, Yuvraj Anandrao Jagtap, Vivek Sharma, Rohan Dhiman, Amit Prasad, Rahul Verma, Subashchandrabose Chinnathambi, Amit Mishra.

  Protein homeostasis is a critical aspect of cellular homeostasis as proteins are one of the most diverse biomolecules, responsible for multiple molecular and cellular functions. Protein quality control machinery is essential for maintaining integrity of cellular proteome via regulating its synthesis, structure, function, and degradation. Molecular chaperones are central to the protein quality control apparatus of cells and assist in folding nascent polypeptides, maturation, sequestration, solubilisation, and degradation of proteins. The coordination and cooperation between multiple cellular chaperones and other quality control elements, such as ubiquitin-proteasome system and autophagy, form a network, critical for proteostasis. Disturbed proteostasis and protein aggregation are hallmark features of neurodegenerative diseases. Re-establishing cellular proteostasis and enhancing chaperones' levels and functions can alleviate protein aggregation and associated cytotoxicity. Here, we have explored the potential of abundant cellular chaperone Hsp90, large chaperone Hsp110, small chaperone Hsp27, and anti-oxidant and mitoprotective chaperone DJ-1 in the regulation of proteostasis, with implications for neurodegenerative diseases, Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis. We have focused on roles and mechanisms of function of these chaperones in countering disturbed proteostasis in neurodegenerative disorders.

Keywords:  Alzheimer’s; Amyotrophic lateral sclerosis; DJ-1; Hsp110; Hsp27; Hsp90; Huntington’s; Neurodegeneration; Parkinson’s; Proteostasis

DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.033
Mol Neurobiol. 2026 Mar 31. pii: 537. [Epub ahead of print]63(1):

Extracellular Protein Quality Control in Tau Pathology.

Prasun Kumar Bhunia, Deepanshu Verma, Priyanka Vimal, Prasad Kasturi.

  Aging is the primary risk factor for neurodegenerative diseases that are marked by the accumulation of misfolded and aggregated proteins, commonly known as proteinopathies. Among these, tauopathies are the disorders characterized by abnormal tau protein aggregation that are particularly significant in Alzheimer's Disease. Tau protein undergoes pathological post-translational modifications that promote its aggregation into neurofibrillary tangles, which disrupt neuronal function and cognitive decline. Tau can also spread between neurons via extracellular pathways in a prion-like manner, accelerating disease progression. Extracellular protein quality control (PQC) mechanisms modulate this process by balancing tau stability and clearance. However, age-related decline in these PQC systems enhances toxic tau assemblies, their extracellular accumulation and widespread dissemination. This review explores tau secretion, propagation, and extracellular protein quality control (PQC) in maintaining tau homeostasis, aiming to identify therapeutic strategies for tauopathies.

Keywords:  Aging; Extracellular; Neurodegeneration; Proteostasis; Tau

DOI:  https://doi.org/10.1007/s12035-026-05834-8
Neurosci Bull. 2026 Mar 28.

Decode the Ubiquitinome in Parkinson's Disease: From Pathological Aggregates to Targeted DUB Therapeutics.

Xi Yu, Qinshuai Ni, Litong Han, Shenghan Zhang, Huamin Xu, Junxia Xie, Yingjuan Liu.

  Parkinson's disease (PD), a neurodegenerative disorder, is significantly influenced by genetic predispositions, aging, and environmental factors. Central to PD pathology are mechanisms such as aberrant α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, and ferroptosis, all of which are closely associated with dysregulated protein post-translational modifications. Ubiquitination, a critical reversible modification, acts as a pivotal bridge connecting the ubiquitin-proteasome system and the lysosomal-autophagy pathway, with its dynamics finely counterbalanced by deubiquitinating enzymes (DUBs). Notably, under pathological conditions, many DUBs exacerbate disease by stabilizing toxic α-syn aggregates and suppressing mitophagy. This review synthesizes current knowledge on how ubiquitin signaling orchestrates PD pathogenesis and highlights the emerging therapeutic potential of targeting specific DUBs with small molecule inhibitors to restore proteostasis and mitochondrial quality control, offering novel strategies for disease modification in PD.

Keywords:  Deubiquitinating enzymes; Mitophagy; Parkinson disease; Ubiquitination; α-synuclein

DOI:  https://doi.org/10.1007/s12264-026-01613-6
Nat Neurosci. 2026 Mar 30.

UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration.

Yang Liu, Zhiyuan Huang, Yu-Wen Hsu, Pragney Deme, Ashley M Frankenfield, Suheng Wu, Xiaofeng Zhao, Honghe Liu, Tao Zhang, Elizabeth J Alexander, Mingming Liu, Yanjun Zhang, Haocheng Wang, Yixin Zhou, Mervyn J Monteiro, Ling Hao, Norman J Haughey, Jiou Wang.

Protein homeostasis and lipid metabolism are essential processes frequently disrupted in neurodegenerative diseases. However, their mechanistic intersection in disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remains unclear. Ubiquilin 2 (UBQLN2) is a protein quality control factor linked to ALS/FTD. Through multi-omic analyses of induced pluripotent stem cell (iPSC)-derived neurons harboring disease-associated UBQLN2 mutations, we uncovered UBQLN2 as a molecular hub linking lipid dysregulation and proteostasis, the perturbation of which contributes to neurodegeneration. UBQLN2 mediated the degradation of ILVBL (acetolactate synthase-like protein) and ALDH3A2 (aldehyde dehydrogenase 3 family member A2), two enzymes essential for mitochondrial lipid catabolism associated with lipid droplets and neuronal viability. ALS/FTD-linked UBQLN2 mutations and TAR DNA-binding protein 43 (TDP-43) pathology impair the degradation of ILVBL and ALDH3A2, leading to metabolic dysfunction and neurodegeneration. Restoring the UBQLN2-ILVBL/ALDH3A2 axis attenuates neurodegenerative phenotypes in neurons, organoids and mice, establishing UBQLN2 as a critical regulator of metabolic homeostasis in ALS/FTD and other related neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41593-026-02226-y
ACS Chem Neurosci. 2026 Mar 30.

Transient Interactions of α-Synuclein N- and C-Termini.

Lei Ortigosa-Pascual, Noemi Ferrante Carrante, Katja Bernfur, Katarzyna Makasewicz, Emma Sparr, Sara Linse.

  α-Synuclein (αSyn) is a neuronal protein predominantly found at the synapse, involved in vesicle trafficking. αSyn aggregates are also the main component of Lewy bodies, the hallmarks of Parkinson's disease. Interactions between the N- and C-termini of αSyn play crucial roles in its behavior in solution, membrane binding, and aggregation. Studying these interactions provides valuable insights into the physiological and pathological functions of αSyn. Here, we employed photoinduced cross-linking of unmodified proteins (PICUP) to identify the transient contacts of αSyn in different conformational states. By using tyrosine-to-phenylalanine mutations to block the reactivity of specific amino acids, we establish key cross-links in each state. In solution, we identify internal contacts between the N- and C-termini of monomers, as well as intermonomer contacts between C-termini in oligomers. When αSyn is bound to membranes, the internal cross-linking is blocked, while the cross-linking between C-terminal regions persists. In fibrils, cross-linking is significantly reduced, primarily occurring between the C-termini of adjacent monomers. This work highlights the effectiveness of PICUP for reporting on the transient contacts involved in αSyn self-assembly and its coassembly with lipid membranes, while providing a streamlined protocol that opens avenues for studying protein-protein interactions for a wide range of systems.

Keywords:  coassembly; cooperativity; intermediates; peripheral membrane protein; self-assembly

DOI:  https://doi.org/10.1021/acschemneuro.6c00108
J Am Chem Soc. 2026 Apr 01.

Electric Double Layer Phenomena Near Surfaces Irreversibly Trigger Assembly of Tau Protein.

Eloise Masquelier, Madeline Hicks, Nicholas Watkins, Norleakvisoth Lim, Justin Yi, Daniel E Morse, Lior Sepunaru, Michael J Gordon.

The reversible folding and assembly of the human brain protein tau are regulated by charge neutralization through limited and reversible phosphorylation, enabling tau to bind tubulin and maintain the structural integrity of neuronal microtubules. However, in neurodegenerative diseases like Alzheimer's and related tauopathies, tau becomes hyperphosphorylated, detaches from tubulin, and irreversibly assembles into β-structured amyloid filaments responsible for neuronal death. In previous work, we showed that charge neutralization via Faradaic electroreduction of cationic residues in tau and other intrinsically disordered proteins can mimic phosphorylation to trigger protein condensation, folding, and assembly. Here, we demonstrate that even non-Faradaic effects─including large electric fields and concentration gradients in the electric double layer, together with spatial ordering of ions at the solution-electrode interface─can induce folding and assembly of tau, its microtubule-binding region K18, and a 19-residue tau peptide (jR2R3 P301L) containing a mutation known to induce early aggregation in vitro and in vivo. Assembly occurs on different electrode materials at identical effective electric fields, demonstrating independence from the electrode hydrophobicity and electronic structure. Surface-enhanced infrared absorption and plasmon resonance spectroscopies show that near-surface electric fields of ∼1 MV/cm trigger K18 folding and assembly. Ion ordering and charge screening near electrodes at higher salt concentrations (50 vs 1 mM) also reduce Coulombic repulsion between protein monomers and their cationic residues, promoting folding and assembly. Overall, these results show that interfacial electric fields and other non-Faradaic processes can reveal and drive protein misfolding and aggregation, hallmarks of tauopathies and prion-related neurodegenerative diseases.

DOI: https://doi.org/10.1021/jacs.5c23171
Front Aging Neurosci. 2026 ;18 1780247

Molecular mechanisms underlying exercise-enhanced autophagy in improving neuroplasticity in Alzheimer's disease.

Qian Li, Renqing Zhao, Xin Tian, Haocheng Xu.

  Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by progressive memory impairment and cognitive dysfunction. The neuropathological hallmarks of this neurodegenerative disorder encompass two principal pathological features: extracellular deposition of amyloid-β (Aβ) plaques due to abnormal protein aggregation, and intracellular accumulation of neurofibrillary tangles (NFTs) caused by hyperphosphorylation of tau proteins (p-Tau). These pathological changes induce synaptic loss and neuronal apoptosis, which leads to impaired neuroplasticity and progressive deterioration of cognitive function. Autophagy, a critical mechanism in the central nervous system (CNS) responsible for clearing misfolded protein aggregates and damaged organelles, plays a pivotal role in maintaining neuronal homeostasis and synaptic plasticity. However, AD is associated with autophagy impairment, resulting in the accumulation of toxic protein aggregates and damaged organelles. These pathological changes disrupt protein homeostasis, thereby exacerbating neurodegenerative processes. Currently, AD therapeutic strategies remain limited. Emerging evidence indicates that exercise intervention mitigates cognitive decline and enhances synaptic plasticity, potentially through reducing Aβ deposition and pathological phosphorylation of tau proteins. However, the precise mechanisms through which these interventions act remain to be fully elucidated. Recent studies have shown that exercise can promote autophagosome formation, fusion, and lysosomal hydrolytic function, thereby ameliorating the pathological progression of AD. Despite these promising findings, the precise molecular targets and underlying signaling mechanisms through which exercise modulates autophagy in AD remain to be fully elucidated. The purpose of this study is to establish innovative therapeutic targets while identifying mechanistically actionable pharmacological targets to advance therapeutic development against AD pathogenesis.

Keywords:  Alzheimer’s disease; autophagy; cognitive functions; exercise; neuroplasticity

DOI:  https://doi.org/10.3389/fnagi.2026.1780247
Adv Protein Chem Struct Biol. 2026 ;pii: S1876-1623(25)00128-2. [Epub ahead of print]150 489-517

Tau-Cytoskeleton and their interaction with other neurodegenerative proteins.

Surajita Sahu, Nagaraj Rangappa, Subashchandrabose Chinnathambi, Monalisa Mishra.

  A wide range of neurological conditions known as Tauopathies are distinguished by a peculiar accumulation of Tau protein and its effect on the central nervous system (CNS) and beyond. In Tauopathies, Tau aggregation has a primary role in the neurodegenerative process. Clinically, individuals exhibit various symptoms, such as cognitive or behavioural anomalies, mobility issues, memory loss, and language problems. The major Tau isoforms (3R, 4R, or an equal 3R:4R ratio) identified in the inclusion bodies of the brain are used to classify Tauopathies pathologically. We address various Tauopathies, differentiating between primary and secondary forms, the involvement of Tau isoforms, the affected brain areas, and the corresponding neuropathological features. This review emphasizes the pathological and physiological role of Tau protein, providing a comprehensive analysis of the molecular processes enabling Tau aggregation and its subsequent effect on neuronal structure and function. Additionally, the review highlights the complex interactions that exist between Tau and other neurodegenerative proteins, including amyloid-beta in Alzheimer's disease, alpha-synuclein in Parkinson's disease, huntingtin protein in Huntington's disease, and how these relationships worsen Tau pathology and advance neurodegeneration. The organ-specific impact of Tauopathy, including the brain and other peripheral organs, has been discussed. The significance of these findings for future treatment techniques aiming at addressing Tau disease and mitigating its organ-specific repercussions.

Keywords:  Alpha-synuclein; Huntingtin; Peripheral organs; Tau; β-Amyloid

DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.032
Adv Protein Chem Struct Biol. 2026 ;pii: S1876-1623(25)00115-4. [Epub ahead of print]150 423-443

Pathological microtubule dynamics in Parkinson's disease: Mechanisms and therapeutic implications.

Kirti Baghel, Ateendra Kumar Dubey, Satyendra Singh, Vijay Kumar Prajapati.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily marked by the degeneration of dopaminergic neurons in the substantia nigra and the pathological accumulation of misfolded α-synuclein in Lewy bodies. This chapter explores the underrecognized role of microtubule (MT) dysregulation in PD pathogenesis, linking disruptions in cytoskeletal integrity to impaired axonal transport and neuronal survival. The fundamental biology of MTs, their dynamics, and their regulation by motor proteins and associated proteins like MT-associated proteins (MAPs), tau, and gamma-tubulin complexes. Special attention is given to how mutations linked to PD, such as those in SNCA (α-synuclein), Parkin, PINK1 (PTEN-induced kinase 1), and LRRK2 (leucine-rich repeat kinase 2), lead to MT destabilization, impaired mitophagy, and disruptions in axonal transport. A self-perpetuating cycle of MT disruption and α-synuclein aggregation is proposed, resulting in synaptic failure and dopaminergic neuron loss. The chapter also evaluates emerging therapeutic strategies targeting MT stabilization, including LRRK2 inhibitors, MT-stabilizing agents like Epothilone D, and approaches to modulate α-synuclein aggregation. Challenges such as the blood-brain barrier, off-target effects of MT-targeting drugs, and patient-specific variability in drug response are critically discussed. The future directions include CRISPR-Cas9-based gene therapies and personalized medicine, emphasizing the need for a deeper understanding of PD-related molecular pathways. This comprehensive overview highlights MT dynamics not just as collateral damage but as a central element in PD pathology, offering novel insights into potential avenues for intervention.

Keywords:  Cytoskeletal integrity; Microtubule dysregulation; PINK1-parkin mitophagy pathway; Parkinson’s disease; α-synuclein aggregation

DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.019
Adv Protein Chem Struct Biol. 2026 ;pii: S1876-1623(25)00122-1. [Epub ahead of print]150 397-422

The quest to restore neuronal structure: Targeting cytoskeletal proteins in neurodegenerative diseases.

Chandrabose Selvaraj, Deepali Desai, Elayaperumal Sumitha.

  Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease are characterized by progressive neuronal dysfunction and loss. A growing body of evidence implicates cytoskeletal disruption as a central pathological mechanism in these conditions. Cytoskeletal proteins, including microtubules, actin filaments, tau, neurofilaments, and alpha-synuclein, not only provide structural integrity but also regulate axonal transport, synaptic connectivity, and neuroplasticity. Its dysfunction will lead to impaired intracellular trafficking, protein aggregation, and neuronal degeneration. This chapter explores clearly about the specific cytoskeletal abnormalities that are evident in major neurodegenerative disorders, highlighting the biological mechanisms such as tauopathy-induced microtubule instability in Alzheimer's, actin cytoskeleton dysregulation in Parkinson's, and neurofilament aggregation in ALS. Current therapeutic strategies aimed at the stabilizing cytoskeletal components, enhancing protein clearance, and restoring transport dynamics are examined, alongside the cutting-edge approaches including the gene therapy, CRISPR/Cas9 editing, and nanotechnology-based delivery systems. Challenges such as limited blood-brain barrier penetration, off-target toxicity, and patient heterogeneity are also discussed with the focus on need for precision medicine. Additionally, we have also explored the future directions that specifically focused on the biomarker development, combination therapies, and strategies to promote neuroregeneration and structural plasticity. Targeting cytoskeletal pathways holds significant promise not only for suppressing the disease progression but also for rebuilding the structural foundation of the nervous system, potentially reversing the neurodegenerative decline.

Keywords:  Brain; Cytoskeletal proteins; Neurodegenerative diseases; Neuronal degeneration; Neuronal dysfunction

DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.026
Chem Res Toxicol. 2026 Mar 30.

Incense Aerosol-Induced Neurotoxicity Disrupts α-Synuclein Homeostasis in a Cellular Parkinson's Disease Model, Distinct from Cigarette Aerosols.

Yi-En Tseng, Ming-Chu Teng, Yu-Siou Huang, Chia-Hsuan Pan, Yuan-Pin Chang, Chia C Wang, Hsiu-Fang Fan.

Incense burning is a widespread indoor combustion practice, yet its neurotoxic potential and impact on α-synuclein (α-Syn) proteostasis remain poorly defined. Using SH-SY5Y cells overexpressing α-Syn as a cellular Parkinson's disease model, we exposed cells to size-fractionated incense aerosol extracts (IAE) prepared as organic-phase (OP) or water-soluble phase (WP). α-Syn overexpression augmented vulnerability to IAE, producing greater losses in viability and pronounced increases in intracellular hydrogen peroxide (H2O2), mitochondrial membrane potential depolarization, and engagement of programmed cell-death pathways. Live-cell fluorescence cross-correlation spectroscopy (FCCS) revealed that both OP-IAE and WP-IAE shifted α-Syn from oligomeric to monomeric states in the cytosol, indicating disruption of oligomerization equilibrium. Antioxidant intervention revealed mechanistic differences compared with other indoor air pollutants, cigarette smoke. OP-IAE-induced cytotoxicity cannot be mitigated by N-acetylcysteine (NAC) or rutin, whereas WP-IAE-induced toxicity was partially attenuated, with NAC surpassing rutin. By contrast, for cigarette aerosol extracts (CAE), both OP- and WP-CAEs were robustly rescued by NAC and, to a lesser extent, rutin. Together, these results indicate that incense aerosols, particularly OP-IAE, engage reactive oxygen species (ROS)-linked mitochondrial injury and programmed cell-death pathways while uniquely driving α-Syn monomerization, while exhibiting relative resistance to classical antioxidant intervention compared with cigarette aerosols. This work points out incense smoke as a distinct indoor neurotoxicant with implications for α-Syn homeostasis and Parkinsonian risk in exposed populations.

DOI: https://doi.org/10.1021/acs.chemrestox.6c00091
CNS Neurol Disord Drug Targets. 2026 Mar 30.

Neuroinflammation, Autophagy, and Neurodegeneration: Mechanisms and Therapeutic Insights.

Pukar Khanal, Abhishek Balmik.

  Neuroinflammation and autophagy dysregulation are critical in the pathogenesis of neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's disease. Neuroinflammation occurs after a sustained immune response, which transitions into a chronic pathological state, leading to the sustained generation of pro-inflammatory cytokines and oxidative stress, causing neuronal damage. Meanwhile, defective autophagy exacerbates disease by promoting protein accumulation, e.g., amyloid-β, tau, and α-synuclein, thereby enhancing neuroinflammation. In this review, we focus on critical pathways, including mTOR and AMPK, that regulate these events and illustrate how their dysregulation may lead to a vicious cycle of inflammation and autophagy dysfunction. Novel therapeutic strategies, including mTOR inhibitors, autophagy enhancers, and inflammasome modulators, may contribute to cellular homeostasis. Furthermore, approaches that promote upregulation of chaperone- mediated autophagy can enable selective clearance of mediators of inflammatory response and aggregated/misfolded proteins. Advanced approaches such as CRISPR-based gene editing and RNA therapeutics provide tools to target molecular mechanisms involved in these neurodegenerative disorders, whereas the development of reliable biomarkers and novel delivery strategies may pave the way for personalized treatments. Moreover, artificial intelligence-based workflows and models may strengthen phenotypic and mechanistic screening of autophagy modulators and potential drug targets. By incorporating these forthcoming insights, this review underscores the critical need for comprehensive therapies that target both neuroinflammation and autophagy dysfunction to mitigate disease progression and improve patient outcomes.

Keywords:  Autophagy; molecular pathways; neurodegeneration; neurodegenerative diseases; neuroinflammation; therapeutic targets.

DOI:  https://doi.org/10.2174/0118715273440234260304000039