Associations of Alzheimer's disease biomarker progression with cognitive decline are important to inform patient prognosis. Of particular interest is how newly available plasma biomarkers evolve relative to cognitive dec...Associations of Alzheimer's disease biomarker progression with cognitive decline are important to inform patient prognosis. Of particular interest is how newly available plasma biomarkers evolve relative to cognitive decline. The goals of this work are to measure how much earlier vs later an individual's progression on plasma and PET Alzheimer's disease biomarkers is associated with earlier vs later cognitive progression and to estimate the average timeline of progression of these processes in the population. In this cohort study of 2369 Mayo Clinic Study of Aging (MCSA) and 1591 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, we fit non-linear mixed effects models to estimate how much earlier vs later each individual progresses on plasma p-tau217, amyloid PET, tau PET, and auditory verbal learning test (AVLT) sum of trials relative to the population mean (individual adjustment), the associations of these individual adjustments among biomarker pairs, and how covariates affect the timing of biomarker progression. The association of individual adjustments implies mechanistic associations and the amount of variability in cognitive decline accounted for by each biomarker. By applying cutpoints, we also estimated the relative timing that these biomarkers become abnormal in the population. Associations of individual adjustments were moderate between all biomarkers and AVLT (R=0.38-0.47) in the MCSA and stronger (R=0.74-0.81) in ADNI; plasma p-tau217 accounted for 16% of the variability in timing of AVLT decline in the MCSA and 64% in ADNI. APOE ɛ4 carriership was associated with earlier biomarker progression. AVLT became abnormal after the biomarkers up to age 90, after which AVLT was estimated to become abnormal prior to tau biomarkers. The association of the timing of plasma and PET AD biomarker progression with cognitive decline was modest in the MCSA population-based sample and stronger in the Alzheimer's disease-enriched ADNI cohort. The timing of plasma p-tau217 progression explained a similar degree of variability in AVLT progression as amyloid PET, supporting its utility as a marker of disease progression. The estimated temporal ordering of biomarkers and cognitive abnormality was as anticipated (amyloid, tau, cognition) up to the age of 90, beyond which AVLT was estimated to become abnormal prior to tau biomarkers, likely related to the effects of non-Alzheimer's disease co-pathologies.
Xu F, Zhang R, Li Y
… +17 more, Wang H, Zhao Z, Li H, Shen X, Chen P, Jin X, Wu E, Cui X, Zhang D, Li C, Chen X, Chen R, Xi JJ, Sun J, Yang Y, Luo J, Zhang S
Pain is an unpleasant sensory and emotional experience that can lead to anxiety and attention deficit. Hitherto, effective therapies for pain remain limited. Although multiple factors were reported to modulate the pain,...Pain is an unpleasant sensory and emotional experience that can lead to anxiety and attention deficit. Hitherto, effective therapies for pain remain limited. Although multiple factors were reported to modulate the pain, few studies have explored the neural mechanisms of long non-coding RNA (lncRNA) in pain. Here, we identified a high expression level of Carip in the lateral parabrachial nucleus (LPBN), which participates in modulating pain-like behaviors. Thermal stimulation can induce the significant upregulation of lncRNA Carip in the LPBN neurons. The knock-out (KO) of Carip elevates pain thresholds. Electrophysiological assays in LPBN→CeA neurocircuit demonstrated that Carip KO simultaneously increased the amplitude of evoked AMPAR excitatory postsynaptic currents (eEPSCs) and evoked GABAAR inhibitory postsynaptic currents (eIPSCs), disrupting of the neuronal excitation and inhibition (E/I) balance due to the enhanced phosphorylation of synapsin1 Ser9 via protein kinase A dependent signaling cascade in LPBN neurons, which is deemed as the crucial reason for abnormal pain-like behaviors. Importantly, blocking the Carip-mediated intracellular signaling cascade by specific knockdown of synapsin1 (synapsin1 KD) or PKA (PKA KD) in LPBN neurons of Carip KO mice not only restores the E/I balance but also ameliorates the abnormal pain-like behaviors. Together, our study demonstrates the important roles of Carip in pain-like behaviors, and suggests that modulating E/I balance by Carip-mediated intracellular signaling pathway could effectively alleviate pain. Our studies provide the synaptic and molecular explanations of how Carip modulates pain-like behaviors.
White TA, Camm EJ, Rock CR
… +12 more, Sutherland AE, Pham Y, Castillo-Melendez M, Dudink I, Ahmadzadeh E, Dean J, Palmer KR, Malhotra A, Guo T, Allison BJ, Miller SP, Miller SL
The rate of human brain growth is greatest in mid-to-late fetal gestation, corresponding to peak neuronal dendritogenesis. In pregnancies complicated by fetal growth restriction (FGR) caused by placental dysfunction, bra...The rate of human brain growth is greatest in mid-to-late fetal gestation, corresponding to peak neuronal dendritogenesis. In pregnancies complicated by fetal growth restriction (FGR) caused by placental dysfunction, brain development is adversely impacted, with evidence of reduced total and hippocampal brain volume in childhood and cognitive deficits. The cellular basis for hippocampal maldevelopment and dysfunction in FGR is unknown. In this study we employed complementary preclinical and clinical investigations of hippocampal developmental trajectory in growth restricted neonates to address this knowledge gap. In the preclinical study (FGR n=18, control n=19), FGR was induced in fetal sheep via surgical induction of placental insufficiency at 89 days gestational age (dGA, term is 148dGA), and after near-term birth (136dGA), postnatal memory function was measured over four weeks. Neuronal dendritogenesis (dendrite length, branching, complexity) was assessed using Golgi-Cox staining of individual hippocampal Cornu Ammonis (CA)1 neurons at two neonatal timepoints, newborn age at 24 hours after birth and 4-weeks of age, to compare the trajectory of hippocampal neuron development in FGR and control lambs. Results show that, in control lambs, total dendrite length and branching of CA1 hippocampal neurons significantly increased between newborn age and 4-weeks. In FGR lamb brains, neither dendrite length or branching increased over this period, and dendrite deficits were worse in FGR lambs at 4-weeks, corresponding to reduced hippocampal area. In 4-week-old lambs, we observed a significant correlation between total dendrite length of CA1 neurons and memory function. Hippocampal growth trajectory and function deficits were corroborated in small for gestational age (SGA) infants born very preterm. Magnetic resonance imaging (MRI) was performed in very preterm infants in early life, and repeated at term equivalent age, showing that the trajectory of anterior hippocampal growth was significantly reduced in SGA infants (n=20) compared to appropriate for gestational age (AGA; n=139) infants. Within the SGA infant cohort, reduced anterior hippocampal volume was significantly associated with lower Bayley Cognitive Composite scores at 18 months corrected age, controlling for gestational age at birth and infant sex. Together, these findings demonstrate that the trajectory of hippocampal growth is significantly impaired in SGA/FGR infants, caused by disturbed neuronal dendritogenesis that is programmed by an adverse fetal environment and persists, or worsens, after birth. Results in the clinical cohort provide the critical link between programming of reduced dendritogenesis, hippocampal volume deficit and cognitive dysfunction in SGA infants.
Cowley J, Harrison N, Pegg A
… +34 more, Chan H, Li Z, Kaur A, Welsh E, Brewin A, Carlos Yam-Puc J, Fensome G, Broome E, Morano IM, Jinks E, Grafton G, Cooper AJ, Ahmed Z, Stevens AR, Anderson FG, Wykes V, Chelvarajah R, Tsermoulas G, Ughratdar I, Zisakis A, O'Halloran PJ, Davies DJ, Land T, Chowdhury YA, Sher Z, Yakoub KM, Bergin C, Galloway L, Upthegrove R, Brady CA, Gordon J, Qureshi O, Belli A, Barnes NM
Traumatic brain injury (TBI) is a major cause of death throughout the world and currently there are no approved drugs to treat this debilitating condition emphasising the clear unmet substantial clinical need. It is well...Traumatic brain injury (TBI) is a major cause of death throughout the world and currently there are no approved drugs to treat this debilitating condition emphasising the clear unmet substantial clinical need. It is well recognised that microglial activation and the hostile neuroinflammatory response arising after the initial insult provides a therapeutic window for pharmacological intervention. The purinergic P2X7 receptor (P2X7R) is a key driver of neuroinflammation in a range of animal models of TBI. To generate translational evidence for the role of the P2X7R, we optimised two human inflammatory models; human cells (monocyte-derived microglia (hMDM)) in vitro and human brain tissue ex vivo, to test the impact of clinical-stage brain-penetrant P2X7R antagonists. Using lipopolysaccharide (LPS)-primed hMDM, the P2X7R agonist, BzATP, evoked a concentration-dependent increase in pro-inflammatory IL-1β and IL-18 release, which was antagonised in a concentration-dependent manner by selective P2X7R antagonists, and also inhibitors of either the NLRP3 complex or caspase-1, implicating a role for the inflammasome in P2X7R-mediated cytokine release. Using slices of human brain tissue, BzATP similarly evoked cytokine release in a concentration-dependent manner that was also antagonised by selective P2X7R antagonists at pharmacologically relevant concentrations. The present study demonstrates the ability of P2X7R antagonists to suppress the neuroinflammatory response from primed hMDM and human brain slices to offer direct translational data that central P2X7R antagonism may limit pathology-driven pro-inflammatory responses in the brain. This is predicted to improve the clinical outcomes for patients with TBI and other neuroinflammatory pathologies.
Amyotrophic lateral sclerosis(ALS) is a devastating neurodegenerative disorder with limited therapeutic interventions. Neuroinflammation represents a central pathogenic mechanism in ALS, yet the upstream molecular regula...Amyotrophic lateral sclerosis(ALS) is a devastating neurodegenerative disorder with limited therapeutic interventions. Neuroinflammation represents a central pathogenic mechanism in ALS, yet the upstream molecular regulators that integrate multiple inflammatory cascades remain poorly understood. Here, we investigated whether Bruton's tyrosine kinase (BTK), which integrates DNA-sensing and Toll-like receptor signals upstream of the cGAS-STING-NF-κB cascade, serves as a key regulatory node in ALS pathogenesis. Public RNA-seq datasets of motor neurons and post-mortem tissues from ALS patients were utilized to identify BTK expression patterns. SOD1-mutant human induced pluripotent stem cells (hiPSC) were differentiated into motor neurons (hiPSC-MNs) and microglia (hiPSC-MGs). NF-κB dysregulation was profiled by scRNA-seq (hiPSC-MGs) and bulk RNA-seq (hiPSC-MNs). DNA damage (γH2AX), inflammatory signalling (western blot/ELISA) and phagocytosis (pH-rodo uptake) were quantified, and MG-conditioned medium was tested for MN toxicity. Monocultures and MN-MG co-cultures received zanubrutinib (3 µM, 12 h). SOD1-G93A mice were administered zanubrutinib (30 mg/kg, daily) from 2.5 months; motor performance, survival, spinal histology and PI3K-AKT-mTOR activity were assessed after 2 months of treatment. ALS spinal cord and cortex tissues of patients, as well as SOD1-mutant hiPSC-MGs and hiPSC-MNs, demonstrated elevated BTK phosphorylation with increased p-STING, p-TBK1, and nuclear NF-κB accumulation. ALS hiPSC-MGs exhibited inflammatory activation, NLRP3 induction, and impaired phagocytosis, while ALS hiPSC-MNs showed DNA damage and caspase-3-mediated apoptosis. Conditioned medium from inflammatory microglia amplified neuronal STING-NF-κB activity and apoptosis, demonstrating non-cell-autonomous toxicity. The STING inhibitor H-151 reduced neuronal p-STING/p-TBK1/NF-κB and apoptosis, confirming pathway causality. Pharmacological BTK inhibition reduced DNA damage in ALS hiPSC-MNs by 61.4% (p<0.05), restored phagocytosis in ALS hiPSC-MGs to 87.2% of control levels (p<0.01), and prevented neuronal apoptosis induced by microglial conditioned medium. In SOD1-G93A mice, BTK blockade extended median survival from 158 to 173 days (p<0.01, log-rank test), improved motor function, and attenuated neuroinflammation while moderately rebalancing PI3K-AKT-mTOR signaling without impairing autophagy-lysosome dynamics. We identify BTK as a critical upstream regulator of the dysregulated cGAS-STING-NF-κB signalling axis characteristic of ALS pathogenesis. BTK orchestrates both cell-autonomous dysfunction in motor neurons and non-cell-autonomous toxicity through microglial activation, representing a convergent regulatory node that integrates multiple pathogenic pathways. These mechanistic insights provide a molecular framework for understanding ALS neuroinflammation and establish a rational basis for BTK-targeted therapeutic intervention in neurodegeneration.
Lagartos-Donate MJ, Escobar-Doncel B, Zhang SQ
… +19 more, Pan JP, Villaseca González N, Anisimov A, Montaldo NP, Jensen V, Mao L, Li B, Banzon-Pereira N, Shi L, Cao SQ, Caponio D, Wang P, Nair RR, Luo OJ, Chen G, Nevado-Holgado AJ, Buckley N, Nilsen HL, Fang EF
Downregulation and inactivation of the Repressor Element 1-Silencing Transcription factor (REST) is shown in Alzheimer's disease (AD) and likely contributes to its progression, but the exact molecular mechanism linking R...Downregulation and inactivation of the Repressor Element 1-Silencing Transcription factor (REST) is shown in Alzheimer's disease (AD) and likely contributes to its progression, but the exact molecular mechanism linking REST reduction to AD remains unclear. We examined changes in REST expression in the entorhinal cortex and hippocampus across different Braak stages of tauopathy. We show that alterations in REST expression and sub-cellular localization are partially responsible for AD pathology, as REST overexpression improves cognition, reduces amyloid-β and phosphorylated Tau deposition, and restores mitochondrial and synaptic homeostasis. Mechanistically, the NAD+/SIRT1 axis modulates REST expression through chromatin remodelling in the promoter region of REST, leading to changes in the expression of REST target genes involved in mitophagy and synaptic function. These findings reveal a new mechanism of action for NAD+ and highlight REST as a promising therapeutic target for AD therapy.
Okubo M, Ogawa M, Eura N
… +13 more, Inoue YU, Dewa KI, Owa T, Miyashita S, Murakami T, Nakamura H, Hayashi S, Nonaka I, Ogata K, Hoshino M, Inoue T, Nishino I, Noguchi S
Mutations in the SNUPN gene, which encodes snurportin-1, a nuclear import adaptor for U1 small nuclear ribonucleoproteins (snRNP), have recently been implicated in limb-girdle muscular dystrophy, attributed to disrupted...Mutations in the SNUPN gene, which encodes snurportin-1, a nuclear import adaptor for U1 small nuclear ribonucleoproteins (snRNP), have recently been implicated in limb-girdle muscular dystrophy, attributed to disrupted pre-messenger RNA splicing in skeletal muscle. U1 small nuclear ribonucleoproteins play a vital role in pre-messenger RNA splicing, a process essential for transcript fidelity and the regulation of gene expression across tissues. However, the impact of SNUPN mutations on the CNS remains unclear. We identified pathogenic variants in the SNUPN gene in two families with spinocerebellar atrophy. One patient exhibited mild changes in skeletal muscle, while the other did not. To elucidate the pathogenic mechanisms, nuclear transport of the mutated snurpotin-1, and its interaction with importin beta were analysed in vitro. Then, we generated a knock-in mouse carrying the patients' variants and assessed its motor function and cerebellar morphology in vivo. Furthermore, we analysed U1 snRNP localization and RNA splicing in cerebellar Purkinje cells by both RNA- and single-cell RNA sequencing. Mutated snurportin-1 displayed impaired nuclear transport and reduced binding to importin beta. The knock-in mouse mimicking the compound heterozygous variants exhibited cerebellar ataxia, cerebellar atrophy and dendritic abnormalities in Purkinje cells. Abnormal RNA splicing and reduced expression were observed in many genes related to neuronal development and synaptic organization in Purkinje cells, leading to an immature cytoskeleton and reduced secretion of sonic hedgehog. The defects in Purkinje cells caused secondary abnormalities in granule cell migration and interneuron development. Our findings suggest that snurportin-1 plays a critical role in cerebellar development through U1 snRNP-mediated RNA processing and that its dysfunction may contribute to spinocerebellar ataxia. These results expand the clinical spectrum of SNUPN-related disorders beyond skeletal muscle and highlight splicing dysregulation as a potential mechanism underlying cerebellar atrophy.
Missense mutations in CACNA1A, which encodes CaV2.1 voltage-gated calcium channels, underlie serious neurological diseases with inadequate treatment options. Developing new therapies for CACNA1A diseases is hindered by:...Missense mutations in CACNA1A, which encodes CaV2.1 voltage-gated calcium channels, underlie serious neurological diseases with inadequate treatment options. Developing new therapies for CACNA1A diseases is hindered by: 1) unknown biophysical impact of many mutations, 2) limited knowledge of genotype effects on channel function and behavioural phenotype, and 3) dearth of animal models mimicking the human disease. Here, we focus on a CACNA1A missense mutation (D1634N) identified in a patient with ataxia, epilepsy, moderate intellectual disability, and mild cerebellar loss. Heterologously expressed D1634N channels displayed a significantly decreased whole-cell current amplitude, a +25-mV shift in activation V1/2, and diminished single-channel open probability, indicating a loss-of-function (LoF). Patient-specific cortical neurons derived from induced pluripotent stem cells displayed enhanced intrinsic excitability compared to isogenic controls. Heterozygous knock-in mice with the analogous mutation (D1585N) displayed ataxia, absence epilepsy, and cognitive deficits, mirroring the human behavioural phenotype. Purkinje cell and cerebellar slice electrophysiology revealed a reduced whole-cell CaV2.1 current with a right-shifted V1/2 of activation, altered Purkinje cell excitability, and changes in presynaptic vesicle release probability at the parallel fibre to Purkinje neuron input. The results introduce a new CACNA1A LoF mutation and highlight the power of combined heterologous expression, iPSC neurons, and animal model studies to provide complementary insights into the molecular basis of disease with implications for developing therapies.
Parkinson's disease is an age-related neurodegenerative disease that is characterized by the deposition of α-synuclein aggregates in the brain. Nevertheless, the molecular mechanisms that regulate α-synuclein aggregation...Parkinson's disease is an age-related neurodegenerative disease that is characterized by the deposition of α-synuclein aggregates in the brain. Nevertheless, the molecular mechanisms that regulate α-synuclein aggregation have not yet been fully identified. TMEM106B is a lysosomal transmembrane protein that has been reported to be associated with brain aging and neurodegenerative diseases including Parkinson's disease. Here we show that TMEM106B is reduced in the brains of patients with Parkinson's disease. Knockdown of TMEM106B increases the formation of α-synuclein aggregates in primary neurons and mouse brains. TMEM106B deficiency results in impaired lysosomal acidification, lipid metabolism disorders, and lipid droplet deposition in neurons. Interestingly, lipid droplets promote α-synuclein aggregation, resulting in the formation of α-synuclein fibrils with enhanced seeding activity and neurotoxicity compared with α-synuclein fibrils formed in the absence of lipid droplets. TMEM106B deficiency also leads to retardation of α-synuclein degradation by reducing the enzymatic activity of the lysosomal protease cathepsin D. Taken together, these results indicate that TMEM106B deficiency contributes to Parkinson's disease pathogenesis by accelerating α-synuclein aggregation and halting α-synuclein degradation.
Hupalo D, McCauley JL, Gomez L
… +56 more, Griswold AJ, Hoher G, Konidari I, Lorenzo J, Parker GS, Pascual J, Sandford AR, Whitehead PL, Davis DA, Garamszegi S, Gultekin SH, Sun X, Vontell RT, Chatigny M, Chernicky D, Constant MM, Darling IG, Ennulat DJ, Esposito JM, Morris K, Lawton ES, Morakabati NR, Oduor P, Rodgers AP, Sang LA, Sullivan KM, Tabit CJ, Turpin T, Zeabi A, Zheng T, Berretta S, Klengel T, Ruzicka WB, Oakley DH, Blanchard T, Ho E, Johnson R, LeFevre A, Bustamante M, Haroutunian V, Marino C, Purohit DP, Wysocki M, Glausier JR, Lewis DA, Nagra RM, Alba C, Martin J, Rice E, Rosenberger J, Smith G, Sukumar G, Tompkins M, Wilkerson MD, Dalgard CL, Scott WK
CNS diseases are a prevailing cause of morbidity and mortality worldwide, and are influenced by environmental and biological factors, including genetic risk. Here, we generated genome-wide genetic data on a large cohort...CNS diseases are a prevailing cause of morbidity and mortality worldwide, and are influenced by environmental and biological factors, including genetic risk. Here, we generated genome-wide genetic data on a large cohort of brain tissue donors with in-depth clinical and neuropathological phenotyping, allowing for broad investigations into the risk and mechanisms of these neurological, neurodevelopmental, and psychiatric conditions. This resource consists of 9,663 donors with array-based genotyping and 9,543 donors with whole-genome sequencing completed. The clinical diagnoses of these donors include 148 central nervous system diseases clustered into 15 broad categories by International Classification of Diseases-10 (ICD-10) coding. These donors were collected by six repositories comprising the National Institutes of Health NeuroBioBank, with an average participant age of 60 years. While primarily older individuals of European descent, the cohort also contains younger donors and individuals from non-European backgrounds. Variants were detected in whole-genome sequencing (WGS), normalized and annotated to describe their functional impact, resulting in 171,121,209 unique variants and 1,078,774 non-silent variants. These raw and normalized data have been made available as a neurogenomics resource in the National Institute of Mental Health Data Archive (NIMH NDA) (nda.nih.gov), combined with donor-matched deep demographic and phenotypic data from the NeuroBioBank Portal (neurobiobank.nih.gov). To illustrate applications, we replicated the strong association observed in previous studies between pathogenic CAG nucleotide repeat expansions in the HTT gene with the clinical diagnosis of Huntington's disease, as well as associations of the APOE gene with Alzheimer's disease, and examined the association of polygenic risk scores with the three most common disease diagnoses in the cohort.
Rollot F, Casey R, Kerbrat A
… +39 more, Edan G, Le Page E, Vukusic S, Mathey G, Maillart E, De Sèze J, Ciron J, Ruet A, Labauge P, Papeix C, Zephir H, Lebrun-Frenay C, Defer G, Moreau T, Berger E, Clavelou P, Heinzlef O, Thouvenot E, Pelletier J, Casez O, Bourre B, Wahab A, Moulin S, Kwiatkowski A, David T, Magy L, Camdessanché JP, Doghri I, Dos Santos A, Hankiewicz K, Sarov Riviere M, Manchon E, Pottier C, Tchikviladze M, Scherer Gagou C, Dahan C, Durozard P, Laplaud DA, Michel L
The impact of high-efficacy therapies (HET) on progression independent of relapse and MRI activity (PIRMA) remains poorly defined. In this context, using the French MS registry, we aimed to assess the real-life effective...The impact of high-efficacy therapies (HET) on progression independent of relapse and MRI activity (PIRMA) remains poorly defined. In this context, using the French MS registry, we aimed to assess the real-life effectiveness of HET compared with moderate-efficacy therapies (MET) on PIRMA in patients with relapsing-onset multiple sclerosis. Data were collected from patients with relapsing-onset multiple sclerosis of the French MS registry, between January 2010 and June 2023, with a mean follow-up of 3.7 years. Patients with relapsing-onset multiple sclerosis were included in the analysis if they were treated first with HET (2666 included) or MET (7833 included) and had expanded disability status scale and MRI follow-up every 2 years. Each outcome was studied using a propensity score framework. The primary outcome was time to first PIRMA. Secondary outcomes were PIRMA incidence, time to first confirmed disability progression, relapse-associated worsening (RAW), MRI-associated worsening (MAW) and identification of risk factors associated with PIRMA. A total of 10 499 patients fulfilled the inclusion criteria. The mean and standard deviation (SD) age at treatment initiation was 36.4 (10.3) years, with a mean (SD) disease duration of 3.1 (5.1) years. The restricted mean (SD) survival time to first PIRMA was slightly, but significantly shorter in the HET group compared with the MET group [8.7 (0.08) versus 8.9 (0.05) years, P = 0.017]. However, when looking at time to first confirmed disability progression, it tend to be longer in the HET group compared with the MET group [7.6 (0.10) versus 7.3 (0.06) years, P = 0.071], and it was probably linked to the shorter time to first RAW and MAW in the MET group [9.2 (0.06) versus 8.7 (0.05) years, P < 0.001 for RAW; and 9.0 (0.05) versus 8.5 (0.07) years, P < 0.001 for MAW]. Baseline risk factors associated with increased PIRMA incidence in the whole population were high expanded disability status scale, higher age at baseline and the presence of spinal cord lesions. Even if HET gives better control on disability accumulation related to disease activity than MET, our real-life study suggests that PIRMA-related mechanisms are not differentially affected by HET versus MET.
Ray A, Chia R, Rasheed M
… +9 more, Bayram E, International MSA Genomics Consortium
, Dickson DW, Traynor BJ, Gibbs JR, Dalgard CL, Ross OA, Houlden H, Scholz SW
The human X chromosome accounts for ∼5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omissi...The human X chromosome accounts for ∼5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omission of sex chromosomes from genome-wide association studies. This study used whole-genome sequencing data from 888 multiple system atrophy (MSA) cases and 7,128 controls to perform an X-chromosome-wide common variant association study. Our analyses revealed two sex-differential risk loci: one located at Xq28, associated with increased risk for MSA in females (index variant: rs4898389, odds ratio [OR] = 1.69, 95% confidence interval [CI] = 1.40-2.03, p-value = 2.43×10⁻⁸), and another at Xp22.2 within the TBL1X gene, identified in males (index variant: rs6638956, OR = 1.48, 95%CI = 1.26-1.73, p-value = 9.92×10⁻⁷). In the Xq28 locus, colocalization analyses pointed to FAM3A and PLXNA3 as genes of interest. These findings emphasize the vital role of sex-differential genetic factors in the pathogenesis of MSA.
Johari M, Folland C, Saito Y
… +63 more, Oud MM, Parmar JM, Töpf A, Kurbatov S, Ampleeva M, Zakharova EY, Chekmareva IA, Shirokova KS, Atiakshin D, van Beek R, Gardeitchik T, Kamsteeg EJ, Medici E, Donker Kaat L, Nemoto J, Komaki H, Okabe T, Kimoto Y, Tokito T, Nakanowatari M, Oya Y, Bruels CC, Stafki SA, Estrella EA, Littel HR, Kunkel LM, Kang PB, Osei-Owusu I, Pais L, O'Leary M, Austin-Tse C, O'Donnell-Luria A, Mangilog B, Genetti CA, Valivullah ZM, Radio FC, D'Amico A, Ciolfi A, Tartaglia M, Perrin A, Van Goethem C, Sole G, Martin-Négrier ML, Cossée M, Milic Rasic V, Kovacevic G, Kosac A, Moreno CAM, Gontijo Camelo C, Zanoteli E, Habib C, Fahey MC, Beggs AH, Poulsen NS, Vissing J, Straub V, Savarese M, Tasca G, Voermans NC, Laing NG, Udd B, Nishino I, Ravenscroft G
Tubulinopathies encompass a spectrum of disorders resulting from variants in genes encoding α- and β-tubulins, the key components of microtubules. While previous studies have linked de novo or dominantly inherited TUBA4A...Tubulinopathies encompass a spectrum of disorders resulting from variants in genes encoding α- and β-tubulins, the key components of microtubules. While previous studies have linked de novo or dominantly inherited TUBA4A missense variants to neurodegenerative phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, spastic ataxia, and recently, an isolated congenital myopathy, the full phenotypic and genotypic spectrum of TUBA4A-related disorders remains incompletely characterised. In this multi-centre study, we identified one previously reported and 12 novel TUBA4A missense variants in 31 individuals from 19 unrelated families. Remarkably, individuals in 17 families presented with a myopathy without any CNS involvement or history of such disease. In the remaining two families, we observed probands with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness along with protein aggregation. The coexistence of neuromuscular and neurodegenerative features with protein aggregation defines a multisystem proteinopathy. These two families thus establish the first association between TUBA4A and multisystem proteinopathy. Our cohort exhibited diverse genotypes and inheritance patterns: four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A, three probands had recessive inheritance due to homozygous variants, while the respective heterozygous carriers were asymptomatic; five probands carried de novo variants, and nine probands with heterozygous variants were classified as sporadic cases. Clinical phenotypes ranged from mild to severe myopathy, predominantly affecting the axial and paraspinal muscles. We observed a range of disease onset, from congenital to late adulthood. Creatine kinase levels were variable, ranging from normal to highly elevated. Cardiac function remained preserved across the cohort. Muscle biopsies showed heterogenous myopathic changes, including myofibre size variation, nemaline bodies, core-like regions, and internal nuclei. Immunohistochemical analysis revealed protein accumulations positive for TDP-43 (n=2), p62 (n=5), and TUBA4A (n=6). Complementary in silico and in vitro investigations suggested that the identified TUBA4A variants cause significant protein abnormalities and may differentially impact microtubule dynamics. Correlation analyses integrating clinical severity, variant location, and mechanistic readouts further demonstrated that domain specificity within TUBA4A influences both the pattern of muscle involvement and the extent of microtubule disruption. Our findings establish myo-tubulinopathies as distinct clinical entities, encompassing both primary myopathies and multisystem proteinopathies with muscle involvement. This study broadens the phenotypic and genotypic spectrum of TUBA4A-related disorders beyond autosomal dominant or de novo mechanisms and neurodegenerative presentations. These results underscore the importance of considering TUBA4A variants in the differential diagnosis of axial myopathies and multisystem proteinopathies, regardless of central nervous system (CNS) involvement.
The perineuronal net is a unique extracellular matrix mostly located around certain neurons in the central nervous system, predominantly encompassing parvalbumin-positive interneurons and pyramidal neurons in specific br...The perineuronal net is a unique extracellular matrix mostly located around certain neurons in the central nervous system, predominantly encompassing parvalbumin-positive interneurons and pyramidal neurons in specific brain areas. Composed of characteristic molecular constituents such as chondroitin sulfate proteoglycans, hyaluronan, tenascins, and link proteins, the perineuronal net plays a critical role in modulating various aspects of neuronal and cognitive functions. Accumulating evidence has demonstrated its involvement in ion homeostasis, protection against oxidative stress and inflammation, and the regulation of synaptic plasticity. In addition, several regulatory factors are essential for preserving the structural integrity and physiological functions of the perineuronal net. Importantly, dysregulation of the perineuronal net has been implicated in the pathophysiology of various neurological and psychiatric disorders. Therefore, elucidating the mechanisms underlying the perineuronal net regulation may offer novel therapeutic strategies for treating neurological conditions that currently lack effective interventions. This review summarizes recent advances in the perineuronal net research and underscores its emerging physiological, clinical, and therapeutic relevance.
This scientific commentary refers to ‘High-resolution electrophysiological mapping of effective connectivity of lateral prefrontal cortex’ by Avalos-Alais (https://doi.org/10.1093/brain/awaf317).This scientific commentary refers to ‘High-resolution electrophysiological mapping of effective connectivity of lateral prefrontal cortex’ by Avalos-Alais (https://doi.org/10.1093/brain/awaf317).
Small extracellular vesicles (sEVs) efficiently transport pathological RNAs in ischemic stroke, yet whether penumbral hypoxia-induced EVs deliver pathogenic cargo to remote regions, impacting acute ischemic stroke outcom...Small extracellular vesicles (sEVs) efficiently transport pathological RNAs in ischemic stroke, yet whether penumbral hypoxia-induced EVs deliver pathogenic cargo to remote regions, impacting acute ischemic stroke outcomes, remains unclear. Using a focal ischemia mouse model, we isolated brain-derived EVs (BDEVs) from the cortical penumbra and determined their pathological impact on synaptically connected remote regions. In vitro, penumbra BDEVs (PEVs) exacerbated recipient neuronal damage, intensifying apoptosis and dendritic injury during oxygen-glucose deprivation/reoxygenation. In vivo tracing confirmed PEV transport via anatomical projections to remote thalamic neurons, where internalization triggered synaptic loss and apoptosis in distal thalamic nuclei. Mechanistically, PEVs delivered the penumbra-specific circular RNA CircOGDH through trans-synaptic delivery to connected thalamic neurons, directly inducing synaptic and neuronal injury. Critically, cortical CircOGDH knockdown abolished thalamic CircOGDH accumulation and reversed neuronal loss and synaptic impairment, confirming its causal role in secondary damage. Transcriptomics further revealed PEV enrichment in RNAs dysregulating synaptic and axonal pathways. Thus, we open a new view PEVs initiated a thalamus pathogenic pathway where BDEVs deliver CircOGDH and functional RNAs to drive non-infarcted region degeneration. This redefines remote post-stroke injury as an active RNA trafficking process, highlighting therapeutic opportunities for intercepting EV-mediated trans-synaptic pathology.
Méreaux JL, Wirth T, Davoine CS
… +19 more, Delvallée C, Leitão E, Erdlenbruch F, Cogan G, Jeschonneck N, Méneret A, Grabli D, Ewenczyk C, Lamouche JB, Muller J, Dondaine N, Kaya S, Klebe S, Tranchant C, Depienne C, Brice A, Anheim M, Durr A, NS-Park Essential Tremor Working Group