Biology subjects

Dickson, D. W.

Publications and source records attributed to Dickson, D. W..

At least 19 recordsLinked to original sources

bioRxiv2026

Targeted single-nucleus sequencing of 39,800 neurons reveals extensive low-frequency somatic variants

Recent evidence implicates somatic mutations in disease-associated genes across multiple neurodegenerative disorders, including the identification of two somatic TARDBP variants as a putative cause of frontotemporal lobar degeneration with TDP-43 pathology type C (FTLD-TDP type C). However, these findings remain anecdotal. We performed single-nucleus amplicon sequencing of 39,800 neurons from the superior temporal gyrus of sporadic FTLD-TDP type C patients (34,738 neurons, 52 individuals) and non-demented controls (5,062 neurons, 26 individuals) using the Mission Bio Tapestri platform and investigated somatic variants in TARDBP and other FTLD-TDP-associated genes in a case-control setting. We uncovered an extensive landscape of ultra-low-frequency (<1%) somatic mutations across all analysed genes, including TARDBP. Rare somatic occurrences of known ALS/FTD-associated germline TARDBP variants, including p.N267S and p.M337V, were identified exclusively in patients. Among all targeted genes, TARDBP had the highest proportion of neurons harbouring a somatic variant, and this mutational burden was lower in individuals who died at an older age. Strikingly, the C-terminal domain of TDP-43, where most ALS/FTD germline pathogenic variants reside, exhibited a lower neuronal mutational burden than its other domains. This suggests that neurons harbouring damaging mutations may undergoprogressive loss prior to autopsy, leaving only rare survivors at frequencies too low to detect by bulk or small-scale single-cell approaches. Together, our findings provide an unprecedented resolution into the somatic mutational landscape of post-mitotic neurons in FTLD-TDP type C and reveal a gene-specific layer of neuronal mosaicism that current single-cell WGS studies fail to detect.

genetics↗

bioRxiv2026

TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD

Nuclear depletion of TDP-43 is a defining pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leading to widespread RNA misprocessing, including the formation of cryptic exons. Here, we identified TDP-43 as a regulator of circular RNA (circRNA) biogenesis in multiple human neuronal cell models, and showed that its dysfunction induces the de novo formation of cryptic circular RNAs (c-circRNAs). Analysis of post-mortem brain transcriptomic data identified a subset of c-circRNAs which are specific for ALS and FTD cases with TDP-43 pathology. Further, we developed highly sensitive rolling-circle amplification-based circRNA detection assays that allow to distinguish TDP-43 pathology in human CNS tissues with a 0.99 AUC. We found that c-circRNAs can co-occur with cryptic linear splicing events, uncovering complex RNA misprocessing hotspots that induce loss of disease-relevant proteins, including RPTOR and EHMT1. Notably, one of these c-circRNAs originates from UNC13A, a gene whose cryptic exon has previously been linked to one of the major GWAS hits in ALS/FTD and that is being pursued as a therapeutic target through splice-switching ASOs. We showed that c-circUNC13A is co-regulated with the linear cryptic transcript and suppression of UNC13A cryptic exon results in c-circUNC13A reduction in cultured neurons and in vivo, highlighting its potential as a target engagement biomarker for emerging UNC13A-directed therapies. Overall, this work identifies a novel molecular mechanism for TDP-43 dysfunction, opening novel avenues for understanding disease pathogenesis and developing much needed pathology biomarkers.

neuroscience↗

bioRxiv2026

Targeted proteomics of postmortem human brain reveals neurobiologic heterogeneity in Alzheimer's disease using NULISA technology

BackgroundAlzheimers disease (AD) is clinicopathologically heterogeneous. A proportion of patients living with AD present clinically at a younger onset of cognitive symptoms before 65 years old and/or non-amnestic clinical syndromes. Neuropathologically, corticolimbic distribution of neurofibrillary tangle pathology occurs on a continuum with some cases having greater cortical tau pathology relative to limbic regions and others with relatively restricted accumulation in limbic structures. These patterns of corticolimbic tangle distribution are associated with clinical presentation and age at onset. This study sought to examine protein expression differences across the spectrum of clinicopathologic heterogeneity using the NULISA targeted proteomics platform. MethodsA series of thirteen neuropathologically diagnosed AD cases from Mayo Clinic prospectively followed research studies were selected to reflect heterogeneity of clinical syndromes and corticolimbic distribution of tangle pathology. Frozen postmortem brain tissue samples were isolated from inferior parietal cortex and homogenized in RIPA buffer for analysis using Alamar Biosciences NULISA CNS disease 120 panel. Applying a conservative detection threshold of 75% level of detection for the novel application of NULISA in human brain, we evaluated levels of 69 of 129 protein targets across samples. We examined associations between age at onset cognitive symptoms and corticolimbic distribution of tangles (CLix) separately with individual protein targets using linear regression analysis. ResultsAD cases with a younger age at onset had higher measured levels of ubiquitin, while older age was associated with higher levels of total tau, CRH, and NPTX2. Investigations of corticolimbic heterogeneity revealed AD cases with lower CLix score (i.e., cortical predominant distribution of tau) had higher measured p-tau181, p-tau231, ubiquitin, and p62. AD cases with higher CLix (i.e., relative cortical sparing) had higher levels of total tau, CRH, NPTX2, MDH1, and HBA1. Brain-derived total tau consistently showed a stronger association in both models. ConclusionThis work demonstrates the utility of postmortem proteomics for investigating biomarkers associated with AD clinicopathologic heterogeneity. We observed proteomic differences in synapse integrity, tau post-translational modification, and ubiquitination associated with age at symptomatic onset and corticolimbic distribution of tangle pathology.

neuroscience↗

bioRxiv2026

TDP-43 subtypes shape transcriptomic signatures in Alzheimer's disease

TAR DNA-binding protein 43 (TDP-43) pathology frequently co-occurs with Tau neurofibrillary tangles (NFTs) and amyloid {beta} plaques in Alzheimers disease (AD), driving significant clinical heterogeneity. Whether TDP-43 engages autonomous molecular programs or instead amplifies Tau-driven neurodegeneration remains difficult to resolve, largely because these pathologies often co-occur. To separate these overlapping signatures, we generated regionally resolved transcriptomic profiles from cognitively normal controls (Controls), neuropathologically defined cohorts of AD, AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE), and frontotemporal lobar degeneration (FTLD-TDP), categorizing them by their distinct TDP-43 subtypes (types and {beta} for AD/LATE; types A and B for FTLD-TDP). By integrating transcriptomic profiles with quantitative measures of phosphorylated TDP-43 (pTDP-43) and Tau (pTau), we separated pathology-associated signals within mixed disease contexts. We found that TDP-43 is linked to distinct transcriptomic programs in AD/LATE that are largely uncoupled from Tau burden and diverge from those observed in FTLD-TDP. These signatures showed regional specificity, with transcriptomic remodeling occurring in the amygdala across both diseases, whereas frontal cortex alterations were largely restricted to FTLD-TDP. Furthermore, by stratifying cases by TDP-43 morphological subtype, we unmasked specific biological trajectories, from immune activation to unique cellular vulnerabilities, that are not apparent in unstratified cohorts. Together, our findings provide a framework for decoupling mixed proteinopathies and demonstrate that TDP-43 shapes autonomous, subtype-dependent transcriptional landscapes in AD.

neuroscience↗

bioRxiv2026

Phosphorylated ubiquitin is a secondary messenger and an epigenetic mark mediating mitochondria to nucleus signaling

AbstractParkinsons disease (PD) is commonly associated with dysfunctional mitochondrial homeostasis. PINK1, a S/T kinase mutated in early-onset PD, generates phosphoserine 65 ubiquitin (pS65Ub) on damaged mitochondria facilitating their removal. Here, we show that pS65Ub translocates into the nucleus after generation at damaged mitochondria and is directly attached to substrates by resident E3 ligases. Histone H2A is a major substrate and is modified at lysine 119 (H2AK119) by the polycomb silencer, E3 ligase RING1B. At nucleosomes, pS65Ub simultaneously suppresses RING1B and potentiates H2A deubiquitinases USP16 and USP21. Epigenetic profiling and RNA sequencing reveal that pS65Ub is enriched at the promoters of poorly expressed yet dynamically regulated genes and is associated with H2AK119ub depletion. Functionally, we show that pS65Ub enrichment drives polycomb target gene expression, which accelerates the maturation of dopaminergic neurons. Importantly, post-mortem PD brains exhibit elevated nuclear pS65Ub, potentially linking nuclear pS65Ub accumulation with disease pathogenesis. Together, these data indicate that pS65Ub generated at damaged mitochondria regulates fundamental cellular processes at distant sites.

cell biology↗

bioRxiv2026

Multimodal analysis of cell-free DNA identifies epigenetic biomarkers for amyotrophic lateral sclerosis diagnosis and progression

The role of the epigenome in age-related neurodegenerative disorders remains understudied. Here, we analyzed circulating cell-free DNA (cfDNA) from blood to detect methylation changes as a liquid-biopsy for Amyotrophic Lateral Sclerosis (ALS). Our study included 20 patients with sporadic ALS, 10 patients with C9orf72-associated ALS, 10 asymptomatic carriers of the C9orf72 repeat expansion mutation, and 21 non-disease controls. Following targeted enzymatic methyl-sequencing (EM-seq) of [~]4 million CpG sites, we detected numerous differentially methylated genes, including several implicated in ALS disease risk and pathogenesis. By integrating multiple epigenetic features, we delineated a distinct epigenetic signature, which achieved an average area under the curve (AUC) of 0.91 {+/-} 0.10 upon receiver operator characteristic (ROC) analysis, which enabled detection of [~]70% of ALS patients with close to 100% specificity. Furthermore, we also identified a set of genes whose methylation status significantly correlated with clinical disease progression and cerebrospinal fluid (CSF) neurofilament levels. Our results reveal the potential of cfDNA-based biomarkers to accurately diagnose ALS and potentially predict disease progression.

genetics↗

bioRxiv2026

Accurate strand-specific long-read transcript isoform discovery and quantification at bulk, single-cell, and single-nucleus resolution

Recent advances in long-read transcriptome sequencing enable high-throughput profiling of full-length RNA isoforms in bulk, single-cell, and single-nucleus samples. However, long-read datasets typically contain a mixture of complete and partial transcripts, leading to pervasive ambiguity in read-to-isoform assignment and complicating accurate isoform identification and quantification, particularly in the absence of reliable reference annotations. These challenges are further amplified in single-cell and single-nucleus samples, where coverage is sparse and transcriptional heterogeneity is high. Here, we present the Long Read Alignment Assembler (LRAA), a unified and versatile computational framework for isoform identification and quantification from long-read RNA sequencing data across bulk, single-cell, and single-nucleus transcriptomic samples. LRAA combines splice-graph based structural modeling with expectation maximization based optimization to probabilistically resolve ambiguous read assignments and improve isoform abundance estimation. The framework supports quantification-only, reference-guided, and fully reference-free (de novo) modes of analysis within a single methodological paradigm. We benchmarked LRAA using both simulated and genuine long-read datasets spanning sequencing standards and whole transcriptomes. Central to this evaluation is a novel benchmarking strategy based on Multiplexed Overexpression of Regulatory Factors (MORFs), which provides biologically expressed, barcoded isoforms with unambiguous read-level ground truth. Across all benchmarks, including MORFs, synthetic spike-ins, and whole-transcriptome datasets, LRAA consistently outperformed state-of-the-art methods in isoform identification accuracy, sensitivity, and expression quantification. Finally, we demonstrate the biological utility of LRAA by resolving cell-type-specific isoform usage across peripheral blood immune cell populations and by detecting a pathogenic cryptic isoform of STMN2 with associated transcriptional changes in single-nucleus RNA-seq data from frontal cortex tissue of an individual with frontotemporal dementia (FTD). Together, these results establish LRAA as a robust and general solution for resolving transcript diversity in complex biological systems, from development to disease.

bioinformatics↗

bioRxiv2025

TDP-43 suppression of ATP8A2 cryptic splicing implicates phosphatidylserine-driven neuroinflammation in ALS/FTD

Inappropriate externalization of phosphatidylserine (PS) is a candidate mechanism of pathogenic neuroinflammation, a critical driver of neurodegenerative disease. ATP8A2, a flippase that maintains PS on the plasma membrane inner leaflet, is mutated in both Wabbler-lethal mice and patients with the ataxia syndrome CAMRQ4. Here, we identify ATP8A2 as a target of TDP-43 cryptic exon suppression, and demonstrate that ATP8A2 loss leads to immune-mediated neurodegeneration. ATP8A2 splicing is significantly dysregulated following TDP-43 depletion in human neurons and in brains of patients with Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD). In mice, Atp8a2 loss increases PS exposure and promotes neuroinflammation. Depletion of peripheral macrophages rescues motor axon degeneration and doubles Atp8a2 knockout mouse lifespan, while depletion of both peripheral macrophages and central microglia quadruples lifespan and improves coordination. Hence, ATP8A2 is a pathologically relevant TDP-43 target and inhibition of phagocytic immune cell attack against neurons is a potential treatment for patients with CAMRQ4 and ALS-FTD.

neuroscience↗

bioRxiv2025

TAF15 amyloids propagate via defined motifs in a prion-like fashion

TATA-box binding protein-associated factor 15 (TAF15) is an RNA-binding member of the FET family recently identified as the primary fibrillar constituent in a subset of frontotemporal lobar degeneration (FTLD-FET) cases. Although TAF15 is also linked to amyotrophic lateral sclerosis (ALS), the molecular basis and propagation behavior of its aggregates remain unknown. In this work, we show that recombinant TAF15 forms amyloid fibrils under physiological conditions and developed a single-fluorophore TAF15 biosensor to quantitatively monitor their cellular propagation. Using this system, we demonstrate that both recombinant TAF15 fibrils and pathological aggregates extracted from atypical FTLD with ubiquitin inclusions (aFTLD-U) patient brains seed aggregation efficiently and transmit serially between cells, demonstrating hallmark features of prion-like propagation. Seeding was specific to TAF15 and absent for other amyloidogenic proteins, including the homologous protein fused-in-sarcoma (FUS), revealing an unexpected cross-seeding barrier. Occasional colocalization of FUS within TAF15 inclusions was observed upon transient co-expression, suggesting that FUS can be passively recruited rather than acting as an inducer of pathology in FTLD-FET brains. Computational and peptide-based experimental mapping identified multiple aggregation-prone regions within the TAF15 low-complexity domain that coincide with hotspots stabilizing the core of ex vivo TAF15 amyloid fibrils. These short motifs encode the propagation propensity of TAF15 aggregation in vitro and in cells. Together, these findings establish TAF15 as a bona fide amyloid-forming, prion-like protein and define the sequence grammar underlying its self-assembly, providing a mechanistic framework for its role in FTLD-FET and ALS and offering tractable molecular targets for therapeutic intervention.

biophysics↗

bioRxiv2025

Integrative multiomic analysis links TDP-43-driven splicing defects to cascading proteomic disruption of ALS/FTD pathways

Loss of nuclear TDP-43 is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 is known to regulate RNA processing, including repression of cryptic exons, we currently lack a systems-level understanding of the consequences of TDP-43 loss. To address this, we generated multiomic datasets, including RNA-seq and proteomics, from human iPSC-derived neurons depleted of TDP-43. We found that differentially spliced genes, many expressing cryptic exons, had the greatest protein reductions. Surprisingly, nearly half of differentially expressed proteins were neither mis-spliced, nor differentially expressed genes; most of these also had no reported mis-splicing in seven additional post-mortem and iPSC-derived neuron datasets. Integrative network analysis identified a high-confidence disease-specific subnetwork of over 700 interacting proteins, enriched for mRNA processing, synaptic function, and autophagy. Comparison with post-mortem ALS and FTD samples revealed convergent protein and pathway disruptions. We experimentally validated network-predicted effects of cryptic splicing in ATG4B, STMN2, and DAPK1. Our analyses reveal new TDP-43-dependent molecular cascades and nominate central genes as potential ALS/FTD therapeutic targets.

neuroscience↗

bioRxiv2025

Expanding the spectrum of annexin A11 proteinopathy in frontotemporal lobar degeneration and motor neuron disease

Aggregation of TAR DNA-binding protein 43 (TDP-43) is strongly associated with frontotemporal lobar degeneration (FTLD-TDP), motor neuron disease (MND-TDP), and overlap disorders like FTLD-MND. Three major forms of motor neuron disease are recognized and include primary lateral sclerosis (PLS), amyotrophic lateral sclerosis (ALS), and progressive muscular atrophy (PMA). Annexin A11 (ANXA11) is understood to aggregate in amyotrophic lateral sclerosis (ALS-TDP) associated with pathogenic variants in ANXA11, as well as in FTLD-TDP type C. Given these observations and recent reports of ANXA11 variants in patients with semantic variant frontotemporal dementia (svFTD) and FTD-MND presentations, we sought to characterize ANXA11 proteinopathy in an autopsy cohort of 379 cases with FTLD-TDP, as well as FTLD-MND and MND-TDP cases subclassified neuropathologically into PLS, ALS, and PMA. All FTLD-TDP type C cases had ANXA11 proteinopathy. However, ANXA11 proteinopathy was present in over 40% of FTLD-MND and in 38 out of 40 FTLD-PLS cases (95%), of which 80% had TDP type B or an unclassifiable TDP-43 proteinopathy and 15% had TDP type C. Genetic analyses excluded pathogenic ANXA11 variants in all ANXA11-positive cases. We thus demonstrated novel forms of ANXA11 proteinopathy strongly associated with FTLD-PLS, but not with TDP type C or pathogenic ANXA11 variants. Given the emerging relationship of ANXA11 in TDP-43 proteinopathies, we propose that TDP-43 and ANXA11 proteinopathy (TAP) comprises the molecular pathology of cases with abundant inclusions that are co-immunoreactive for both proteins and we subclassify three types of TAP based on distinct clinical and neuropathologic features.

neuroscience↗

bioRxiv2025

Brain-derived extracellular vesicle microRNAs in Lewy body and Alzheimer's disease

INTRODUCTIONRobust plasma-based biomarkers to distinguish Lewy body disease (LBD) and Alzheimers disease (AD) are currently lacking. We applied track-etch magnetic nanopore (TENPO) sorting for enrichment of brain-derived extracellular vesicle (EV) signatures as potential biomarkers to address this gap. METHODSWe analyzed plasma from 137 autopsy-confirmed patients [30 LBD, 31 AD, 30 AD/LBD, 19 AD with amygdala Lewy bodies (AD/ALB), and 27 controls], sequencing miRNAs from TENPO-isolated GluR2-positive (neuron-enriched) and GLAST-positive (astrocyte-enriched) EVs, and measuring plasma proteins (A{beta}40, A{beta}42, tau, p-Tau181, p-Tau231) via SIMOA. RESULTSWe identified 16 GluR2+, 8 GLAST+, and 4 protein biomarkers with differential expression (false discovery rate-corrected P value < .1) between LBD and AD. A multimodal 15-feature panel classified LBD versus AD with 10-fold cross-validated accuracy = 0.95 and area under the curve (AUC) = 0.96. DISCUSSIONBrain-derived EVs offer accurate and accessible miRNA biomarkers for the differential diagnosis of LBD and AD.

bioengineering↗

bioRxiv2025

The Neurofibrillary Tangle Maturity Scale: A Novel Framework for Tangle Pathology Evaluation in Alzheimer's Disease

Neurofibrillary tangles are dynamic neuropathologic hallmarks of Alzheimers disease with a hypothesized lifespan morphologically-defined by three maturity levels: pretangles, mature tangles, and ghost tangles. To better understand the progression of tangle pathophysiology, we characterized tangle maturity level predilection of 15 tau antibodies recognizing a broad range of linear, phosphorylation, conformational, and truncation epitopes in the hippocampus of 24 postmortem brains. We developed the tangle maturity scoring system to semi-quantitatively evaluate each tangle maturity level. Based on proportions of tangle maturity levels, we classified antibodies as "early" (mostly pretangles and mature tangles), "middling" (mature tangles with pretangles and ghost tangles), and "advanced" (mostly ghost tangles and mature tangles) tangle maturity markers. To summarize tangle maturity predilection, we developed the tangle maturity scale to integrate individual tangle maturity scores. Correlations showed stronger relationships between tangle maturity scale and subsector thickness for more advanced tangle maturity markers in CA1 and subiculum, whereas Braak tangle stage remained consistently correlated throughout markers of the tangle lifespan. To aid in scoring hippocampi, we used machine learning to recognize tangle maturity levels, which performed comparably to a domain expert and showed similar relationships by Spearman correlation. Pattern recognition software was used to assess tangle and neuritic tau burden separately, which generally correlated with Braak stage and neuronal counts. However, tangle-derived tau burden more consistently correlated with hippocampal subsector thickness. In conclusion, we developed manual and automated scoring systems to evaluate tangle maturity levels, demonstrating early 4R, phosphorylated, and oligomeric tau accumulation preceding more advanced 3R and truncated tau. Our study provides supportive evidence of disease-relevant ordering of tau posttranslational modifications in the brain, which may have implications for theragnostic development. These findings underscore the promise of computerized quantitative analyses (i.e., pathomics) for high-throughput feature extraction from whole-slide images to enhance our understanding of microscopically observed morphologic changes.

neuroscience↗

bioRxiv2025

PPM1M, a LRRK2-counteracting, phosphoRab12-preferring phosphatase with potential link to Parkinsons disease

Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking; activating mutations in LRRK2 are linked to Parkinsons disease. Rab phosphorylation is a transient event that can be reversed by phosphatases, including PPM1H, that acts on phosphoRab8A and phosphoRab10. Here we report a phosphatome-wide siRNA screen that identified PPM1M as a phosphoRab12-preferring phosphatase that also acts on phosphoRab8A and phosphoRab10. Upon knockout from cells or mice, PPM1M displays selectivity for phosphoRab12. As shown previously for mice harboring LRRK2 pathway mutations, knockout of Ppm1m leads to primary cilia loss in striatal cholinergic interneurons. We have also identified a rare PPM1M mutation in patients with Parkinsons disease that is catalytically inactive when tested in vitro and in cells. These findings identify PPM1M as a key player in the LRRK2 signaling pathway and provide a new therapeutic target for the possible benefit of patients with Parkinsons disease. TeaserParkinsons linked Rab phosphorylation is reversed by PPM1M; the inactive D440N variant is implicated in rare patient cases.

cell biology↗

bioRxiv2025

Integrative Epigenomic Landscape of Alzheimer's Disease Brains Reveals Oligodendrocyte Molecular Perturbations Associated with Tau

Alzheimers disease (AD) brains are characterized by neuropathologic and biochemical changes that are highly variable across individuals. Capturing epigenetic factors that associate with this variability can reveal novel biological insights into AD pathophysiology. We conducted an epigenome-wide association study of DNA methylation (DNAm) in 472 AD brains with neuropathologic measures (Braak stage, Thal phase, and cerebral amyloid angiopathy score) and brain biochemical levels of five proteins (APOE, amyloid-{beta} (A{beta})40, A{beta}42, tau, and p-tau) core to AD pathogenesis. Using a novel regional methylation (rCpGm) approach, we identified 5,478 significant associations, 99.7% of which were with brain tau biochemical measures. Of the tau-associated rCpGms, 93 had concordant associations in external datasets comprising 1,337 brain samples. Integrative transcriptome-methylome analyses uncovered 535 significant gene expression associations for these 93 rCpGms. Genes with concurrent transcriptome-methylome perturbations were enriched in oligodendrocyte marker genes, including known AD risk genes such as BIN1, myelination genes MYRF, MBP and MAG previously implicated in AD, as well as novel genes like LDB3. We further annotated the top oligodendrocyte genes in an additional 6 brain single cell and 2 bulk transcriptome datasets from AD and two other tauopathies, Picks disease and progressive supranuclear palsy (PSP). Our findings support consistent rCpGm and gene expression associations with these tauopathies and tau-related phenotypes in both bulk brain tissue and oligodendrocyte clusters. In summary, we uncover the integrative epigenomic landscape of AD and demonstrate tau-related oligodendrocyte gene perturbations as a common potential pathomechanism across different tauopathies.

genomics↗

bioRxiv2024

Widespread Distribution of α-Synuclein Oligomers in LRRK2-related Parkinson's Disease

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and sporadic Parkinsons disease (PD). While the clinical features of LRRK2-PD patients resemble those of typical PD, there are significant differences in the pathological findings. The pathological hallmark of definite PD is the presence of -synuclein (SYN)-positive Lewy-related pathology; however, approximately half of LRRK2-PD cases do not have Lewy-related pathology. Lewy-related pathology is a late-stage SYN aggregation that can be visualized with hematoxylin and eosin stains or conventional immunohistochemistry (IHC). Increasing evidence has indicated that SYN oligomers, which represent the early-stage of SYN aggregation, may have neurotoxicity. Visualization of SYN oligomers requires specialized staining techniques, such as SYN-proximity ligation assay (PLA). The distribution and severity of SYN oligomers in the human brain of LRRK2-PD patients remain unknown. In this study, we performed phosphorylated SYN-IHC and SYN-PLA staining on postmortem brain sections of patients with three pathogenic LRRK2 mutants: p.G2019S (n=5), p.I2020T (n=5), and p.R1441C (n=4). The severity of Lewy-related pathology and SYN oligomers were assessed semi-quantitatively in the brainstem, limbic lobe, basal ganglia, and cerebral cortex. SYN oligomers were detected in LRRK2-PD cases even in cases without Lewy-related pathology; a negative correlation was observed between Lewy-related pathology and SYN oligomers (r=-0.26 [-0.39, -0.12]; P<0.0001). Our findings suggest that SYN oligomers may represent a common pathological feature of LRRK2-PD. Notably, patients harboring p.G2019S and p.I2020T had significantly higher levels of SYN oligomers in those without Lewy-related pathology compared to those with Lewy-related pathology. These cases also had a trend toward shorter disease duration. These results imply that in LRRK2-PD, SYN oligomers may initially accumulate in the brain but do not progress to form Lewy-related pathology. The present study suggests that targeting SYN oligomers may be a therapeutic strategy for LRRK2-PD even if there is no Lewy-related pathology.

neuroscience↗

bioRxiv2024

Rod-shaped microglia interact with neuronal dendrites to regulate cortical excitability in TDP-43 related neurodegeneration

Motor cortical hyperexcitability is well-documented in the presymptomatic stage of amyotrophic lateral sclerosis (ALS). However, the mechanisms underlying this early dysregulation are not fully understood. Microglia, as the principal immune cells of the central nervous system, have emerged as important players in sensing and regulating neuronal activity. Here we investigated the role of microglia in the motor cortical circuits in a mouse model of TDP-43 neurodegeneration (rNLS8). Utilizing multichannel probe recording and longitudinal in vivo calcium imaging in awake mice, we observed neuronal hyperactivity at the initial stage of disease progression. Spatial and single-cell RNA sequencing revealed that microglia are the primary responders to motor cortical hyperactivity. We further identified a unique subpopulation of microglia, rod-shaped microglia, which are characterized by a distinct morphology and transcriptional profile. Notably, rod-shaped microglia predominantly interact with neuronal dendrites and excitatory synaptic inputs to attenuate motor cortical hyperactivity. The elimination of rod-shaped microglia through TREM2 deficiency increased neuronal hyperactivity, exacerbated motor deficits, and further decreased survival rates of rNLS8 mice. Together, our results suggest that rod-shaped microglia play a neuroprotective role by attenuating cortical hyperexcitability in the mouse model of TDP-43 related neurodegeneration.

neuroscience↗

bioRxiv2024

Chromogranin A Deficiency Attenuates Tauopathy by Altering Epinephrine Alpha-Adrenergic Receptor Signaling

Our previous studies have indicated that insulin resistance, hyperglycemia, and hypertension in aged wild-type (WT) mice can be reversed in mice lacking chromogranin-A (CgA-KO mice). These health conditions are associated with a higher risk of Alzheimers disease (AD). CgA, a neuroendocrine secretory protein has been detected in protein aggregates in the brains of AD patients. Here, we determined the role of CgA in tauopathies, including AD (secondary tauopathy) and corticobasal degeneration (CBD, primary tauopathy). We found elevated levels of CgA in both AD and CBD brains, which were positively correlated with increased phosphorylated tau in the frontal cortex. Furthermore, CgA ablation in a human P301S tau (hTau) transgenic mice (CgA-KO/hTau) exhibited reduced tau aggregation, resistance to tau spreading, and an extended lifespan, coupled with improved cognitive function. Transcriptomic analysis of mice cortices highlighted altered levels of alpha-adrenergic receptors (Adra) in hTau mice compared to WT mice, akin to AD patients. Since CgA regulates the release of the Adra ligands epinephrine (EPI) and norepinephrine (NE), we determined their levels and found elevated EPI levels in the cortices of hTau mice, AD and CBD patients. CgA-KO/hTau mice exhibited reversal of EPI levels in the cortex and the expression of several affected genes, including Adra1 and 2, nearly returning them to WT levels. Treatment of hippocampal slice cultures with EPI or an Adra1 agonist intensified, while an Adra1 antagonist inhibited, tau hyperphosphorylation and aggregation. These findings reveal a critical role of CgA in regulation of tau pathogenesis via the EPI-Adra signaling axis.

neuroscience↗