Neurobiology of Disease最新文献

{"title":"Wirelessly transmitted subthalamic nucleus signals decode endogenous pain levels in Parkinson's disease patients","authors":"Abdi Reza ,&nbsp;Takufumi Yanagisawa ,&nbsp;Naoki Tani ,&nbsp;Ryohei Fukuma ,&nbsp;Takuto Emura ,&nbsp;Satoru Oshino ,&nbsp;Ben Seymour ,&nbsp;Haruhiko Kishima","doi":"10.1016/j.nbd.2025.107235","DOIUrl":"10.1016/j.nbd.2025.107235","url":null,"abstract":"<div><div>Pain is a prominent non-motor symptom of Parkinson's disease (PD); it may appear in various levels (elevated or diminished) during waking hours and substantially reduces quality of life. Although subthalamic nucleus (STN) signal analysis has dramatically advanced our comprehension of PD, the roles of bilateral STN, the relevant biomarkers, and objective recognition of the pain levels in PD patients remain less understood.</div><div>We recorded bilateral STN signals from PD patients implanted with adaptive deep brain stimulation (DBS) systems and collected pain rating series during in-hospital recovery. Patients provided pain annotations prior to surgery that inform the location (specific or non-specific) and PD-association with pain (PD-related or non-PD-related). A machine learning model was trained to classify higher versus lower pain states, from the eight pain annotation series of the six patients, using features derived from STN signals.</div><div>STN activity significantly classified the pain intensity in the PD-related pain group. Feature analysis indicated that STN activity from both sides can impact pain classification, with gamma and beta bands in the contralateral STN and delta and theta bands in the ipsilateral STN exhibiting a prominent role. Our observational study demonstrates a novel approach to decoding pain states and identifying STN biomarkers linked to PD-related pain.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107235"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145828149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain extracellular matrix implications in multiple neurological disorders revealed through a meta-analysis of transcriptional changes","authors":"Hagit Sadis ,&nbsp;Wote Amelo Rike ,&nbsp;David Peles ,&nbsp;Yara Hussein ,&nbsp;Tchelet Stern ,&nbsp;Irit Sagi ,&nbsp;Shani Stern","doi":"10.1016/j.nbd.2026.107263","DOIUrl":"10.1016/j.nbd.2026.107263","url":null,"abstract":"<div><div>Neurological disorders comprise a wide range of illnesses that may affect the central and peripheral nervous systems. Despite their diverse etiologies, many of these disorders present overlapping symptoms. In this study, we sought to generate hypotheses about shared biological mechanisms across neurodegenerative, neuropsychiatric, and neurodevelopmental disorders by analyzing gene expression data and identifying the most consistently dysregulated genes within and between these groups. To provide additional validation, we referenced Genome-Wide Association Studies (GWAS) data, which supported many of the transcriptomic analyses. Our exploratory analysis identified 31 differentially expressed genes shared across these neurological conditions, compared to healthy controls. These genes were significantly enriched in brain extracellular matrix (ECM) pathways, and dysregulation of ECM genes was evident separately in each of the three disorder categories. Notably, <em>SST</em> (Somatostatin), involved in modulating cortical circuits and cognitive function, was the most frequently reported dysregulated gene shared among the three categories of disorders. Furthermore, we observed consistent patterns suggesting that <em>GFAP</em> (glial fibrillary acidic protein), a key intermediate filament in mature astrocytes and a well-known marker of reactive astrocytes, and <em>IFITM3</em> (interferon-induced transmembrane protein 3), a crucial component of the first-line antiviral defense, were on average the most frequently reported genes among the studied disorders. Our study's core findings indicated that shared molecular features may exist across neurological disorders, emphasizing significant differences in the ECM of the central nervous system (CNS) between health and disease.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107263"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to: Dual role of microglia in neuroinflammation and neurodegenerative diseases. [Neurobiology of Disease, Volume 216, November 2025, 107133]","authors":"Amir Ajoolabady ,&nbsp;Bonglee Kim ,&nbsp;Altaf A. Abdulkhaliq ,&nbsp;Jun Ren ,&nbsp;Suhad Bahijri ,&nbsp;Jaakko Tuomilehto ,&nbsp;Anwar Borai ,&nbsp;Johra Khan ,&nbsp;Domenico Pratico","doi":"10.1016/j.nbd.2026.107276","DOIUrl":"10.1016/j.nbd.2026.107276","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107276"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytic lysosome deficits reduce alpha-synuclein degradation and induce the spread of pathology","authors":"Lindsay M. Roth,&nbsp;Olga Morozova,&nbsp;Jan Stöhr,&nbsp;Jason Schapansky","doi":"10.1016/j.nbd.2026.107277","DOIUrl":"10.1016/j.nbd.2026.107277","url":null,"abstract":"<div><div>Parkinson's Disease (PD) is a neurodegenerative disorder that results from a loss of dopaminergic neurons in the substantia nigra. A pathological hallmark of PD is proteinaceous inclusions called Lewy body aggregates, which consist primarily of misfolded neuronal alpha-synuclein (αSyn). PD pathology progression is thought to be driven by a prion-like spread of αSyn aggregates between adjacent neurons; however, the role of other cell types, such as pathology bearing astrocytes, in this process is still elusive.</div><div>αSyn pathology has been observed in PD patient astrocytes, suggesting that astrocytes could be involved in the processing of aggregates. Therefore, we examined the interaction of astrocytes with αSyn pre-formed fibrils (PFFs) and explored how these cells might modulate the spread of seed-competent αSyn in astrocyte–neuron co-cultures. Isolated primary astrocytes rapidly internalized and degraded αSyn PFFs within hours of internalization. Upon exposure to lysosome compromising agents, such as chloroquine or cathepsin B inhibitors leupeptin or CA-074, degradation of αSyn PFFs was significantly reduced. The addition of astrocytes to primary neuron cultures reduced endogenous αSyn aggregation caused by exogenous αSyn PFFs, indicating that astrocytes may mitigate αSyn pathology in the brain. The addition of lysosome-compromised (LC) astrocytes to primary neuron cultures limited this anti-seeding effect. Finally, LC astrocytes, preloaded with PFFs and added to neuronal cultures, induced αSyn pathology in neurons, whereas unimpaired, PFF-preloaded astrocytes did not. These data suggest that astrocytes can modulate and contribute to the spread of αSyn pathology, significantly contributing to PD pathogenesis.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107277"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebellar contributions to cognitive deterioration in Parkinson's disease: Insights from multi-omics and longitudinal data","authors":"Yukun Feng ,&nbsp;Wei Zhang ,&nbsp;Yinhao Xu ,&nbsp;Qi Chang ,&nbsp;Hao Zhou ,&nbsp;Chunmei Wen ,&nbsp;Jingzhe Li ,&nbsp;Xiao Hu ,&nbsp;Yi Xing ,&nbsp;Da Zhang ,&nbsp;Peiyu Huang ,&nbsp;Junjie Zheng ,&nbsp;Weiguo Liu","doi":"10.1016/j.nbd.2026.107275","DOIUrl":"10.1016/j.nbd.2026.107275","url":null,"abstract":"<div><h3>Background</h3><div>Increasing evidence suggests that pathological damage in Parkinson's disease (PD) involves the cerebellum, thus resulting in structural and functional alterations. However, whether these alterations predict the progression of cognitive impairment in PD remains unclear.</div></div><div><h3>Methods</h3><div>We recruited 30 healthy controls and 72 PD patients across different cognitive states with available plasma biomarker data. We used voxel-based morphometry to identify cerebellar atrophy and subsequently performed seed-based whole-brain voxel-wise Granger causality analysis (GCA) on these regions to map cerebello-cerebral effective connectivity. Cerebellar compensatory capacity thresholds were determined through restricted cubic splines and threshold effect analysis. We applied these thresholds to stratify patients in two independent cohorts from the Parkinson's Progression Markers Initiative (<em>n</em> = 106) and an in-house dataset (<em>n</em> = 87); moreover, we conducted Kaplan-Meier survival curve analyses to predict longitudinal cognitive decline risk.</div></div><div><h3>Results</h3><div>Our study revealed cerebellar atrophy in the left Crus I, right Crus II, and right lobule VI. Cross-sectionally, we identified a dynamic functional connectivity alteration pattern and critical threshold with significant differences in phosphorylated tau 217, glial fibrillary acidic protein, and neurofilament light chain. Subsequently, findings from two longitudinal cohorts further revealed that patients exceeding this threshold exhibited a significantly increased risk of cognitive decline over time.</div></div><div><h3>Conclusions</h3><div>Our study indicates that the effective connectivity threshold from Crus I to the inferior frontal gyrus may predict short-term cognitive decline. These findings highlight the role of the cerebellum in PD-related cognitive decline and may provide important insights for early intervention strategies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107275"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HOPS disruption impairs APP trafficking and processing, promoting exosomal secretion of APP-CTFs","authors":"Derk Draper ,&nbsp;Anna E. George ,&nbsp;Tineke Veenendaal ,&nbsp;Suzanne van Dijk ,&nbsp;Elly Z. Soltani ,&nbsp;Paolo Sanzà ,&nbsp;Frederik J. Verweij ,&nbsp;Judith Klumperman ,&nbsp;Ginny G. Farías","doi":"10.1016/j.nbd.2026.107269","DOIUrl":"10.1016/j.nbd.2026.107269","url":null,"abstract":"<div><div>Amyloid precursor protein (APP) is a key player in various neuronal functions but also the source for toxic Aβ that accumulates in the brain of Alzheimer patients. APP trafficking and processing depend on the <em>endo</em>-lysosomal system, but the molecular mechanisms that coordinate these processes remain not fully understood. Here, we studied the HOPS complex, a central regulator of <em>endo</em>-lysosomal maturation. We show that HOPS disruption impairs retromer-mediated recycling of APP to the TGN, resulting in the accumulation of APP in late endosomes. In neurons, this accumulation is spatially restricted to somatodendritic endosomes. These APP-containing endosomes are catalytically inactive and lack the γ-secretase subunit PSEN2. However, they do contain BACE1, which contributes to the build-up of toxic APP C-terminal fragments (APP-CTFs). Notably, loss of HOPS function enhances secretion of APP-CTFs by exosomes, suggesting a potential mechanism for disease propagation. Together, our findings establish a mechanistic link between HOPS loss-of-function and aberrant APP processing, with implications for neurodegeneration.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107269"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145960012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Compensatory circuits in resting-state networks of epilepsy patients with left-sided hippocampus sclerosis","authors":"Silke Kreitz ,&nbsp;Angelika Mennecke ,&nbsp;Andreas Hess ,&nbsp;Sebastian Brandner ,&nbsp;Caroline Reindl ,&nbsp;Hajo Hamer ,&nbsp;Michael Schwarz ,&nbsp;Julie Rösch ,&nbsp;Arnd Dörfler","doi":"10.1016/j.nbd.2026.107264","DOIUrl":"10.1016/j.nbd.2026.107264","url":null,"abstract":"<div><div>Left-sided temporal lobe epilepsy (LTLE) causes bihemispheric dysfunctions in large networks and poor cognitive performance. To address possible compensatory mechanism in the resting-state we investigated the functional alteration in LTLE patients with histologically proven sclerosis in the left hippocampal CA1-field compared to healthy controls.</div><div>Eight drug resistant LTLE-patients and eight sex and age matched healthy controls were included in the study. The patients' hemispherical language and verbal memory function was determined by intracarotid amytal testing. Additional cognitive abilities and depression-like symptoms were collected using standard questionnaires. 7 T-fMRI of the resting-state and graph-theoretical whole-brain analysis including hippocampal subfields enabled sensitive detection of highly specific resting-state modulations without predefinition of regions of interest. Graph-theoretical network parameter were correlated with patients' cognitive performance and depression-like symptoms.</div><div>Functional connectivity of the hippocampus of LTLE patients was reduced interhemispheric and to the cortex. However, the whole-brain functional connectivity was strengthened, indicating a compensating mechanism for the above mentioned reduced hippocampus connectivity. The network's small-world index did not differ between groups. Graph-theoretical node-parameter were lateralized to the left hemisphere, reflecting interhemispheric neuroplasticity. A network component mediated by the left globus pallidus, the right inferior temporal gyrus and the left anterior corona radiata reinforced the functional connectivity between the impaired hippocampus and the bilateral cortex. The graph-theoretical resilience of the globus pallidus was correlated with improved depression-like symptoms. Therefore, we hypothesize, that the observed compensatory circuit reflects an allostatic adaptation of the brain to balance energy and disease-induced environmental stress rather than to improve cognitive impairments.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107264"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Afferent-driven modulation of spinal interneurofn circuits across disease stages in amyotrophic lateral sclerosis","authors":"Sina Sangari ,&nbsp;Alexandra Lackmy-Vallée ,&nbsp;Iseline Peyre ,&nbsp;Pierre-François Pradat ,&nbsp;Véronique Marchand-Pauvert","doi":"10.1016/j.nbd.2026.107270","DOIUrl":"10.1016/j.nbd.2026.107270","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that progressively disrupts voluntary motor command through combined cortical and spinal motor neuron degeneration. However, how spinal circuits reorganize during the disease remains poorly understood, particularly in humans. This study examined the function of excitatory and inhibitory spinal interneuron circuits that control upper and lower limb movements, using non-invasive electrophysiological techniques targeting specific afferent–motoneuron pathways at cervical and lumbar levels. These segments are clinically relevant, as spinal-onset forms constitute the predominant clinical presentation of ALS. We compared patients with ALS at different stages of functional impairment to healthy individuals. Spinal circuits predominantly driven by muscle spindle afferents (group Ia and II) showed, at the group level, a marked reduction in inhibition together with enhanced propriospinal excitation. In contrast, pathways mediated by tendon afferents (group Ib) and cutaneous inputs appeared preserved in unstratified analyses. However, when accounting for disease stage, inhibitory dysfunction emerged as an early feature, whereas excitation increased progressively with functional impairment, and modulations also became detectable in Ib- and cutaneous-driven responses. These findings reveal an afferent- and stage-dependent hierarchy of spinal dysfunction, following a reproducible sequence from early disinhibition to maladaptive excitation. This dynamic pattern mirrors the organization observed in preclinical spinal models and aligns with cortical pathophysiology, where widespread loss of inhibition precedes selective increases in excitation. Together, these results refine the mechanistic understanding of motor network disorganization in ALS and identify inhibitory interneurons as potential therapeutic targets to stabilize spinal network function.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107270"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145979243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperactivity, compulsive-like behaviours, and impaired flexibility in mouse models of Duchenne muscular dystrophy","authors":"Faouzi Zarrouki ,&nbsp;Léa Ceschi ,&nbsp;Rubén Miranda ,&nbsp;Amel Saoudi ,&nbsp;Cyrille Vaillend","doi":"10.1016/j.nbd.2026.107265","DOIUrl":"10.1016/j.nbd.2026.107265","url":null,"abstract":"<div><div>X-linked Duchenne muscular dystrophy (DMD), caused by mutations in a gene coding several dystrophin isoforms from independent promoters, is associated with a range of brain-related comorbidities. Intellectual disability is variably expressed depending on the position of the genetic variants, intelligence quotients being negatively correlated with the number of deficient brain dystrophins. However, the genetic basis of other phenotypes underlying cognitive deficits and neuropsychiatric disorders, such as executive dysfunctions and attention deficit/hyperactivity disorder (ADHD), is still unclear. In this study, we behaviourally characterized two mouse models (<em>mdx</em>^{<em>5Cv</em>,} <em>mdx52</em>) lacking brain dystrophins, Dp427 or Dp427 and Dp140 respectively, which together correspond to about 90% of DMD patients' mutation profiles. We included new paradigms allowing automated, high-throughput, collection of behavioural data from social groups of mice in home-cage conditions. We show that both models display unaltered circadian exploratory activity in such conditions, opposite of the motor inhibition expressed in stand-alone behavioural tests. In contrast, both models variably developed hyperactivity, impulsive and perseverative behaviours, triggered by sudden task-condition changes such as increases in waiting delays to access rewards, with a moderate impact on delay discounting. Cumulative Dp427 and Dp140 deficiency resulted in reduced memory of fear extinction and impaired behavioural flexibility during reversal of the learning-strategy rule in a working-memory task. These results are relevant to the comorbid diagnosis of ADHD across main mutation profiles in DMD; they also highlight a specific contribution of Dp140 deficiency to maladaptive behavioural inflexibility, and provide new genotype-specific outcome measures to probe brain-targeting treatments in future preclinical studies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107265"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A C. elegans model of familial Alzheimer's disease shows age-dependent synaptic degeneration independent of amyloid β-peptide","authors":"Vaishnavi Nagarajan ,&nbsp;Caitlin L. Libowitz ,&nbsp;Brian D. Ackley ,&nbsp;Michael S. Wolfe","doi":"10.1016/j.nbd.2026.107267","DOIUrl":"10.1016/j.nbd.2026.107267","url":null,"abstract":"<div><div>The membrane-embedded γ-secretase complex is involved in the intramembrane cleavage of ∼150 substrates. Cleavage of amyloid precursor protein (APP)-derived substrate C99 generates 38–43-residue secreted amyloid β-peptides (Aβ), with the aggregation-prone 42-residue form (Aβ42) particularly implicated in the pathogenesis of Alzheimer's Disease (AD). However, whether Aβ42 is the primary driver of neurodegeneration in AD remains unclear. Dominant mutations in APP or presenilin—the catalytic component of γ-secretase—cause early-onset familial AD (FAD) and reduce one or more steps in the multi-step processive proteolysis of C99 to Aβ peptides, apparently through stabilization of γ-secretase enzyme-substrate (<em>E</em>-S) complexes. To investigate mechanisms of neurodegeneration in FAD, we developed new <em>C. elegans</em> models co-expressing wild-type or FAD-mutant C99 substrate and presenilin-1 (PSEN1) variants in neurons, allowing intramembrane processing of C99 to Aβ in vivo<em>.</em> We demonstrate that while FAD-mutation of either C99 or PSEN1 leads to age-dependent synaptic loss, proteolytically inactive PSEN1 did not. Designed mutations that allow stable <em>E</em>-S complex formation without Aβ42 or Aβ production likewise result in synaptic degeneration. Moreover, replacement of C99 with variants of a Notch1-based substrate revealed that disrupted processing of another γ-secretase substrate can similarly lead to synaptic degeneration. These results support a model in which synaptic loss can be triggered by toxic, stalled γ-secretase <em>E</em>-S complexes in the absence of Aβ production and not by simple loss of proteolytic function. This new <em>C. elegans</em> system provides a powerful platform to study the role of dysfunctional γ-secretase substrate processing in FAD pathogenesis.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107267"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}