Biology subjects

Dickson, D. W.

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

At least 37 records · Page 2Linked to original sources

bioRxiv2024

The UFMylation pathway is impaired in Alzheimer's disease

BackgroundAlzheimers disease (AD) is characterized by the presence of neurofibrillary tangles made of hyperphosphorylated tau and senile plaques composed of beta-amyloid. These pathognomonic deposits have been implicated in the pathogenesis, although the molecular mechanisms and consequences remain undetermined. UFM1 is an important, but understudied ubiquitin-like protein that is covalently attached to substrates. This UFMylation has recently been identified as major modifier of tau aggregation upon seeding in experimental models. However, potential alterations of the UFM1 pathway in human AD brain have not been investigated yet. MethodsHere we used frontal and temporal cortex samples from individuals with or without AD to measure the protein levels of the UFMylation pathway in human brain. We used multivariable regression analyses followed by Bonferroni correction for multiple testing to analyze associations of the UFMylation pathway with neuropathological characteristics, primary biochemical measurements of tau and additional biochemical markers from the same cases. We further studied associations of the UFMylation cascade with cellular stress pathways using Spearman correlations with bulk RNAseq expression data and functionally validated these interactions using gene-edited neurons that were generated by CRISPR-Cas9. ResultsCompared to controls, human AD brain had increased protein levels of UFM1. Our data further indicates that this increase mainly reflects conjugated UFM1 indicating hyperUFMylation in AD. UFMylation was strongly correlated with pathological tau in both AD-affected brain regions. In addition, we found that the levels of conjugated UFM1 were negatively correlated with soluble levels of the deUFMylation enzyme UFSP2. Functional analysis of UFM1 and/or UFSP2 knockout neurons revealed that the DNA damage response as well as the unfolded protein response are perturbed by changes in neuronal UFM1 signaling. ConclusionsThere are marked changes in the UFMylation pathway in human AD brain. These changes are significantly associated with pathological tau, supporting the idea that the UFMylation cascade might indeed act as a modifier of tau pathology in human brain. Our study further nominates UFSP2 as an attractive target to reduce the hyperUFMylation observed in AD brain but also underscores the critical need to identify risks and benefits of manipulating the UFMylation pathway as potential therapeutic avenue for AD.

neuroscience↗

bioRxiv2024

Alterations of PINK1-PRKN signaling in mice during normal aging

The ubiquitin kinase-ligase pair PINK1-PRKN identifies and selectively marks damaged mitochondria for elimination via the autophagy-lysosome system (mitophagy). While this cytoprotective pathway has been extensively studied in vitro upon acute and complete depolarization of mitochondria, the significance of PINK1-PRKN mitophagy in vivo is less well established. Here we used a novel approach to study PINK1-PRKN signaling in different energetically demanding tissues of mice during normal aging. We demonstrate a generally increased expression of both genes and enhanced enzymatic activity with aging across tissue types. Collectively our data suggest a distinct regulation of PINK1-PRKN signaling under basal conditions with the most pronounced activation and flux of the pathway in mouse heart compared to brain or skeletal muscle. Our biochemical analyses complement existing mitophagy reporter readouts and provide an important baseline assessment in vivo, setting the stage for further investigations of the PINK1-PRKN pathway during stress and in relevant disease conditions.

neuroscience↗

bioRxiv2024

Large- Scale Deep Proteomic Analysis in Alzheimer's Disease Brain Regions Across Race and Ethnicity

AbstractO_ST_ABSIntroductionC_ST_ABSAlzheimers disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within the non-Hispanic White (NHW) population. Here we aimed to provide comprehensive insights into the proteomic landscape of AD across diverse racial and ethnic groups. MethodsDorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) brain tissues were donated from multiple centers (Mayo Clinic, Emory University, Rush University, Mt. Sinai School of Medicine) and were harmonized through neuropathological evaluation, specifically adhering to the Braak staging and CERAD criteria. Among 1105 DLPFC tissue samples (998 unique individuals), 333 were from African American donors, 223 from Latino Americans, 529 from NHW donors, and the rest were from a mixed or unknown racial background. Among 280 STG tissue samples (244 unique individuals), 86 were African American, 76 Latino American, 116 NHW and the rest were mixed or unknown ethnicity. All tissues were uniformly homogenized and analyzed by tandem mass tag mass spectrometry (TMT-MS). ResultsAs a Quality control (QC) measure, proteins with more than 50% missing values were removed and iterative principal component analysis was conducted to remove outliers within brain regions. After QC, 9,180 and 9,734 proteins remained in the DLPC and STG proteome, respectively, of which approximately 9,000 proteins were shared between regions. Protein levels of microtubule-associated protein tau (MAPT) and amyloid-precursor protein (APP) demonstrated AD-related elevations in DLPFC tissues with a strong association with CERAD and Braak across racial groups. APOE4 protein levels in brain were highly concordant with APOE genotype of the individuals. DiscussionThis comprehensive region resolved large-scale proteomic dataset provides a resource for the understanding of ethnoracial-specific protein differences in AD brain.

neuroscience↗

bioRxiv2024

Bridging the Gap: Multi-Omics Profiling of Brain Tissue in Alzheimer's Disease and Older Controls in Multi-Ethnic Populations

INTRODUCTIONMulti-omics studies in Alzheimers disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked African Americans (AA) and Latin Americans (LA), who are disproportionately affected by AD. METHODSTo bridge this gap, Accelerating Medicines Partnership in AD (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors. RESULTSWe generated multi-omics data and curated and harmonized phenotypic data from AA (n=306), LA (n=326), or AA and LA (n=4) brain donors plus Non-Hispanic White (n=252) and other (n=20) ethnic groups, to establish a foundational dataset enriched for AA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSIONInclusion of traditionally underrepresented groups in multi-omics studies is essential to discover the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD.

neuroscience↗

bioRxiv2024

Probe-dependent Proximity Profiling (ProPPr) Uncovers Similarities and Differences in Phospho-Tau-Associated Proteomes Between Tauopathies

Tauopathies represent a diverse group of neurodegenerative disorders characterized by the abnormal aggregation of the microtubule-associated protein tau. Despite extensive research, the precise mechanisms underlying the complexity of different types of tau pathology remain incompletely understood. Here we describe an approach for proteomic profiling of aggregate-associated proteomes on slides with formalin-fixed, paraffin-embedded (FFPE) tissue that utilizes proximity labelling upon high preservation of aggregate morphology, which permits the profiling of pathological aggregates regardless of their size. To comprehensively investigate the common and unique protein interactors associated with the variety of tau lesions present across different human tauopathies, Alzheimers disease (AD), corticobasal degeneration (CBD), Picks disease (PiD), and progressive supranuclear palsy (PSP), were selected to represent the major tauopathy diseases. Implementation of our widely applicable Probe-dependent Proximity Profiling (ProPPr) strategy, using the AT8 antibody, permitted identification and quantification of proteins associated with phospho-tau lesions in well-characterized human post-mortem tissue. The analysis revealed both common and disease-specific proteins associated with phospho-tau aggregates, highlighting potential targets for therapeutic intervention and biomarker development. Candidate validation through high-resolution co-immunofluorescence of distinct aggregates across disease and control cases, confirmed the association of retromer complex protein VPS35 with phospho-tau lesions across the studied tauopathies. Furthermore, we discovered disease-specific associations of proteins including ferritin light chain (FTL) and the neuropeptide precursor VGF within distinct pathological lesions. Notably, examination of FTL-positive microglia in CBD astrocytic plaques indicate a potential role for microglial involvement in the pathogenesis of these tau lesions. Our findings provide valuable insights into the proteomic landscape of tauopathies, shedding light on the molecular mechanisms underlying tau pathology. This first comprehensive characterization of tau-associated proteomes across different tauopathies enhances our understanding of disease heterogeneity and provides a resource for future functional investigation, as well as development of targeted therapies and diagnostic biomarkers.

neuroscience↗

bioRxiv2024

TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes

In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus. TDP-43 loss leads to cryptic exon inclusion but a role in other RNA processing events remains unresolved. Here, we show that loss of TDP-43 causes widespread changes in alternative polyadenylation, impacting expression of disease-relevant genes (e.g., ELP1, NEFL, and TMEM106B) and providing evidence that alternative polyadenylation is a new facet of TDP-43 pathology.

neuroscience↗

bioRxiv2024

Development and characterization of phospho-ubiquitin antibodies to monitor PINK1-PRKN signaling in cells and tissue

The selective removal of dysfunctional mitochondria, a process termed mitophagy, is critical for cellular health and impairments have been linked to aging, Parkinson disease, and other neurodegenerative conditions. A central mitophagy pathway is orchestrated by the ubiquitin (Ub) kinase PINK1 together with the E3 Ub ligase PRKN/Parkin. The decoration of damaged mitochondrial domains with phosphorylated Ub (p-S65-Ub) mediates their elimination though the autophagy system. As such p-S65-Ub has emerged as a highly specific and quantitative marker of mitochondrial damage with significant disease relevance. Existing p-S65-Ub antibodies have been successfully employed as research tools in a range of applications including western blot, immunocytochemistry, immunohistochemistry, and ELISA. However, physiological levels of p-S65-Ub in the absence of exogenous stress are very low, therefore difficult to detect and require reliable and ultrasensitive methods. Here we generated and characterized a collection of novel recombinant, rabbit monoclonal p-S65-Ub antibodies with high specificity and affinity in certain applications that allow the field to better understand the molecular mechanisms and disease relevance of PINK1-PRKN signaling. These antibodies may also serve as novel diagnostic or prognostic tools to monitor mitochondrial damage in various clinical and pathological specimens.

neuroscience↗

bioRxiv2023

Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes

Progressive supranuclear palsy (PSP) is a rare Parkinsonian disorder characterized by problems with movement, balance, cognition, and other symptoms. PSP differs from Alzheimers disease (AD) and other neurodegenerative diseases displaying abnormal forms of the microtubule-associated protein tau ("tauopathies") by the presence of pathology not only in neurons, but also in astrocytes and oligodendrocytes. Genetic contributors may mediate these differences, however much of PSP genetics remains unexplained. Here we conducted the largest genome-wide association study (GWAS) of PSP to date including 2,779 cases (2,595 neuropathologically-confirmed) and 5,584 controls and identified six independent PSP susceptibility loci with genome-wide significant (p < 5x10-8) associations including five known (MAPT, MOBP, STX6, RUNX2, SLCO1A2) and one novel locus (C4A). Integration with cell type-specific epigenomic annotations revealed a unique oligodendrocytic signature that distinguishes PSP from AD and Parkinsons disease. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identified oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, as well as an association with elevated C4A expression in bulk brain tissue which may be driven by increased C4A copy number in PSP cases. Finally, histological studies demonstrated abnormal tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies including epigenomic and eQTL analyses, we identified potential causal roles for variation in MOBP, STX6, RUNX2, SLCO1A2, and C4A in the pathogenesis of PSP.

neuroscience↗

bioRxiv2022

Methylmap: visualization of modified nucleotides for large cohort sizes

Methylmap is a tool developed for visualization of modified nucleotide frequencies per position, especially for large numbers of samples. Various input possibilities are supported, including the standardized BAM/CRAM files containing MM and ML tags. Availability and implementationMethylmap is written in Python3 and available through PyPI and bioconda. The source code is released under MIT license and can be found at https://github.com/EliseCoopman/methylmap.

bioinformatics↗

bioRxiv2022

Divergent impacts of C9orf72 repeat expansion on neurons and glia in ALS and FTD

Neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are strongly influenced by inherited genetic variation, but environmental and epigenetic factors also play key roles in the course of these diseases. A hexanucleotide repeat expansion in the C9orf72 (C9) gene is the most common genetic cause of ALS and FTD. To determine the cellular alterations associated with the C9 repeat expansion, we performed single nucleus transcriptomics (snRNA-seq) and epigenomics (snATAC-seq) in postmortem samples of motor and frontal cortices from C9-ALS and C9-FTD donors. We found pervasive alterations of gene expression across multiple cortical cell types in C9-ALS, with the largest number of affected genes in astrocytes and excitatory neurons. Astrocytes increased expression of markers of activation and pathways associated with structural remodeling. Excitatory neurons in upper and deep layers increased expression of genes related to proteostasis, metabolism, and protein expression, and decreased expression of genes related to neuronal function. Epigenetic analyses revealed concordant changes in chromatin accessibility, histone modifications, and gene expression in specific cell types. C9-FTD patients had a distinct pattern of changes, including loss of neurons in frontal cortex and altered expression of thousands of genes in astrocytes and oligodendrocyte-lineage cells. Overall, these findings demonstrate a context-dependent molecular disruption in C9-ALS and C9-FTD, resulting in distinct effects across cell types, brain regions, and disease phenotypes. One Sentence SummaryC9orf72-associated ALS and FTD showed a distinct pattern of transcriptome changes, with the largest number of affected genes in C9-ALS in astrocytes and excitatory neurons in upper and deep layers.

neuroscience↗

bioRxiv2022

Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer's Disease related proteins

Alzheimers disease (AD) is neuropathologically characterized by amyloid-beta (A{beta}) plaques and neurofibrillary tangles. Main protein components of these hallmarks include A{beta}40, A{beta}42, tau, phospho-tau and APOE. With the exception of the APOE-{varepsilon}4 variant, genetic risk factors associated with brain biochemical measures of these proteins have yet to be characterized. We performed a genome-wide association study in brains of 441 AD patients for quantitative levels of these proteins collected from three distinct fractions reflecting soluble, membrane-bound and insoluble biochemical states. We identified 123 genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD- related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.

genetics↗

bioRxiv2022

Granulocyte Colony Stimulating Factor causes cerebellar deficits and anxiety in a mouse model of CSF-1 receptor-related leukoencephalopathy

Colony stimulating factor (CSF) receptor-1 (CSF-1R)-related leukoencephalopathy (CRL) is an adult-onset, demyelinating neurodegenerative disease caused by autosomal dominant mutations in CSF1R, modeled by the Csf1r+/- mouse. The expression of Csf2, encoding granulocyte- macrophage CSF (GM-CSF) and of Csf3, encoding granulocyte CSF (G-CSF), are elevated in both mouse and human CRL brains. While monoallelic targeting of Csf2 has been shown to attenuate many behavioral and histological deficits of mouse CRL, including cognitive dysfunction and demyelination, the contribution of Csf3 has not been explored. In this manuscript, we investigate the behavioral, electrophysiological and histopathological phenotypes of CRL mice following monoallelic targeting of Csf3. We show that Csf3 heterozygosity normalized the Csf3 levels in Csf1r+/- mouse brains and ameliorated anxiety-like behavior, motor coordination and social interaction deficits, but not their cognitive impairment. Consistent with this, Csf3 heterozygosity attenuated microglial activation in the cerebellum and in the ventral but not in the dorsal hippocampus. Csf3 heterozygosity also failed to prevent demyelination. Csf1r+/- mice exhibited altered synaptic activity in the deep cerebellar nuclei (DCN) associated with increased deposition of the complement factor C1q on glutamatergic synapses and with increased engulfment of glutamatergic synapses by DCN microglia. These phenotypes were significantly ameliorated by monoallelic deletion of Csf3. Our findings indicate that G-CSF and GM-CSF play non-overlapping roles in mouse CRL development and suggest that G-CSF could be an additional therapeutic target in CRL.

neuroscience↗

bioRxiv2022

Amyloid fibrils in frontotemporal lobar degeneration with TDP-43 inclusions are composed of TMEM106B, rather than TDP-43

FTLD is the third most common neurodegenerative condition, following only Alzheimers and Parkinsons diseases. FTLD typically presents in 45-64-year-olds with behavioral changes or progressive decline of language skills. The subtype FTLD-TDP is characterized by certain clinical symptoms and pathological neuronal inclusions detected by TDP-43 immunoreactivity. Here, we extracted amyloid fibrils from brains of four patients, representing four out of five FTLD-TDP subclasses and determined their near-atomic resolution structures by cryo-EM. Unexpectedly, all amyloid fibrils examined are composed of a 135-residue C-terminal fragment of TMEM106B, a lysosomal membrane protein previously implicated as a genetic risk factor for FTLD-TDP. In addition to TMEM106B fibrils, abundant non-fibrillar aggregated TDP-43 is present, as revealed by immunogold labeling. Our observations confirm that FTLD-TDP is an amyloid-involved disease and suggest that amyloid involvement in FTLD-TDP is of protein TMEM106B, rather than of TDP-43.

molecular biology↗

bioRxiv2021

Single Nuclei Transcriptome Reveals Perturbed Brain Vascular Molecules in Alzheimer's Disease

Blood-brain barrier (BBB) dysfunction is well-known in Alzheimers disease (AD), but the precise molecular changes contributing to its pathophysiology are unclear. To understand the transcriptional changes in brain vascular cells, we performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue in 24 AD and control brains resulting in 79,751 nuclei, 4,604 of which formed three distinct vascular clusters characterized as activated pericytes, endothelia and resting pericytes. We identified differentially expressed genes (DEGs) and their enriched pathways in these clusters and detected the most transcriptional changes within activated pericytes. Using our data and a knowledge-based predictive algorithm, we discovered and prioritized molecular interactions between vascular and astrocyte clusters, the main cell types of the gliovascular unit (GVU) of the BBB. Vascular targets predicted to interact with astrocytic ligands have biological functions in signalling, angiogenesis, amyloid {beta} metabolism and cytoskeletal structure. Top astrocytic and vascular interacting molecules include both novel and known AD risk genes such as APOE, APP and ECE1. Our findings provide information on transcriptional changes in predicted vascular-astrocytic partners at the GVU, bringing insights to the molecular mechanisms of BBB breakdown in AD. Graphical AbstractPericytes (yellow), endothelia (salmon) and astrocytes (purple) that form the gliovascular unit (GVU) at the blood brain barrier (BBB) were interrogated for their differentially expressed genes (DEG) and vascular cell (pericyte or endothelia) to astrocyte interactions using single nucleus RNA sequencing (RNAseq) transcriptome obtained from brains of Alzheimers disease (AD) patients and controls. We identified many upregulated (red) or downregulated (blue) DEGs in AD brains in these cell types. These genes have known biological functions in amyloid {beta} (A{beta}) clearance, immune modulation, astrogliosis and neuronal death. Novel predicted interactions were identified between vascular cells and astrocytic DEGs. Collectively, our findings highlight the vast transcriptome changes that occur at the GVU and provide mechanistic insights into BBB dysfunction in AD. This figure was created with Biorender.com. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/474255v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@f48748org.highwire.dtl.DTLVardef@1ddc3f4org.highwire.dtl.DTLVardef@6bfa5eorg.highwire.dtl.DTLVardef@1024506_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Concurrent tau pathologies in frontotemporal lobar degeneration with TDP-43 pathology

AimsAccumulating evidence suggests that patients with frontotemporal lobar degeneration (FTLD) can have pathologic accumulation of multiple proteins, including tau and TDP-43. This study aimed to determine the frequency and characteristics of concurrent tau pathology in FTLD with TDP-43 pathology (FTLD-TDP). MethodsThe study included 146 autopsy-confirmed cases of FTLD-TDP and 55 cases of FTLD-TDP with motor neuron disease (FTLD-MND). Sections from the basal forebrain were screened for tau pathology with phospho-tau immunohistochemistry. For cases with tau pathology on the screening section, additional brain sections were studied to establish a diagnosis. Genetic analysis of C9ORF72, GRN, and MAPT was performed on select cases. ResultsAmong 201 cases, we found 72 cases (36%) with primary age-related tauopathy (PART), 85 (42%) with aging-related tau astrogliopathy (ARTAG), 45 (22%) with argyrophilic grain disease (AGD), and 2 cases (1%) with corticobasal degeneration (CBD). Patients with ARTAG or AGD were significantly older than those without these comorbidities. One of the patients with FTLD-TDP and CBD had C9ORF72 mutation and relatively mild tau pathology, consistent with incidental CBD. ConclusionThe coexistence of TDP-43 and tau pathologies was relatively common, particularly PART and ARTAG. Although rare, individual patients with FTLD can have multiple concurrent proteinopathies. The absence of TDP-43-positive astrocytic plaques may suggest that CBD and FTLD-TDP were independent disease processes in the two patients with both tau and TDP-43 pathologies. It remains to be determined if mixed cases represent a unique disease process or two concurrent disease processes in an individual.

pathology↗

bioRxiv2021

Phosphorylated tau fluid biomarker sites recognize earlier neurofibrillary tangle maturity levels in the postmortem Alzheimer's disease brain

Alzheimers disease (AD) biomarkers have become increasingly more reliable in predicting AD pathology. While phosphorylated tau fluid biomarkers have been studied for over 20 years, there is a lack of deep characterization of these sites in the postmortem brain. Neurofibrillary tangle-bearing neurons, one of the major neuropathologic hallmarks of AD, undergo morphologic changes that mature along a continuum as hyperphosphorylated tau aggregates. To facilitate interpretation of phosphorylated tau sites as an early fluid biomarker, our goal was to characterize which neurofibrillary tangle maturity levels (pretangle, intermediary 1, mature tangle, intermediary 2, and ghost tangle) they recognize. We queried the Florida Autopsied Multi-Ethnic (FLAME) cohort for cases from Braak stages I-VI. We excluded non-AD pathologies and tauopathies. A total of 24 cases, 2 males and 2 females for each Braak stage, were selected. We performed immunohistochemistry on the posterior hippocampus using antibodies directed towards phospho (p) threonine (T) 181, pT205, pT217, and pT231. Slides were digitized to enable quantification of tau burden. To examine differences in regional vulnerability between CA1 and subiculum, we developed a semi-quantitative system to rank the frequency of each neurofibrillary tangle maturity level. We identified all neurofibrillary tangle maturity levels at least once for each phosphorylated tau site. Primarily earlier neurofibrillary tangle maturity levels (pretangle, intermediary 1, mature tangle) were recognized for all phosphorylated tau sites. There was an increase in tau burden in the subiculum compared to CA1; however, this was attenuated compared to thioflavin-S positive tangle counts. On a global scale, tau burden generally increased with each Braak stage. These results provide neurobiologic evidence that these phosphorylated tau fluid biomarker sites are present during earlier neurofibrillary tangle maturity levels. This may help explain why these phosphorylated tau biomarker sites are observed before symptom onset in fluids.

neuroscience↗

bioRxiv2021

TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration

Triggering receptor expressed on myeloid cell 2 (TREM2) is a surface receptor that, in the central nervous system, is exclusively expressed on microglia. TREM2 variants have been linked to increased risk for neurodegenerative diseases, but the functional effects of microglial TREM2 remain largely unknown. To this end, we investigated TAR-DNA binding protein 43 kDa (TDP-43)-related neurodegenerative disease via viral-mediated expression of human TDP-43 protein (hTDP-43) in neonatal and adult mice or inducible expression of hTDP43 with defective nuclear localization signals in transgenic mice. We found that TREM2 deficiency impaired microglia phagocytic clearance of pathological TDP-43, and enhanced neuronal damage and motor function impairments. Mass cytometry analysis revealed that hTDP-43 induced a TREM2-dependent subpopulation of microglia with high CD11c expression and higher phagocytic ability. Using mass spectrometry and surface plasmon resonance analysis, we further demonstrated an interaction between TDP-43 and TREM2, in vitro and in vivo, in hTDP-43-expressing transgenic mouse brains. We computationally identified the region within hTDP-43 that interacts with TREM2 and observed the potential interaction in ALS patient tissues. Our data reveal the novel interaction between TREM2 and TDP-43, highlighting that TDP-43 is a possible ligand for microglial TREM2 and the interaction mediates neuroprotection of microglial TREM2 in TDP-43-related neurodegeneration.

neuroscience↗

bioRxiv2021

Single-cell profiling of the human primary motor cortex in ALS and FTLD

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two devastating and fatal neurodegenerative conditions. While distinct, they share many clinical, genetic, and pathological characteristics1, and both show selective vulnerability of layer 5b extratelencephalic-projecting cortical populations, including Betz cells in ALS2,3 and von Economo neurons (VENs) in FTLD4,5. Here, we report the first high resolution single-cell atlas of the human primary motor cortex (MCX) and its transcriptional alterations in ALS and FTLD across ~380,000 nuclei from 64 individuals, including 17 control samples and 47 sporadic and C9orf72-associated ALS and FTLD patient samples. We identify 46 transcriptionally distinct cellular subtypes including two Betz-cell subtypes, and we observe a previously unappreciated molecular similarity between Betz cells and VENs of the prefrontal cortex (PFC) and frontal insula. Many of the dysregulated genes and pathways are shared across excitatory neurons, including stress response, ribosome function, oxidative phosphorylation, synaptic vesicle cycle, endoplasmic reticulum protein processing, and autophagy. Betz cells and SCN4B+ long-range projecting L3/L5 cells are the most transcriptionally affected in both ALS and FTLD. Lastly, we find that the VEN/Betz cell-enriched transcription factor, POU3F1, has altered subcellular localization, co-localizes with TDP-43 aggregates, and may represent a cell type-specific vulnerability factor in the Betz cells of ALS and FTLD patient tissues.

neuroscience↗