Karthick Natarajan

Brain Iron as a Surrogate Biomarker of Pathological TDP-43 Identifies Brain Region-Specific Signatures in Ageing, Alzheimer’s Disease and Amyotrophic Lateral Sclerosis Background TDP-43 pathology is a defining feature of several neurodegenerative diseases, but its prevalence and regional distribution in ageing and disease are not well characterised. We investigated ...

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Preprint: CD200R1 loss in CNS-associated macrophages triggers T cell-driven neurodegeneration in Parkinson’s disease
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Clues to Alzheimer Disease in the Newborn Brain This Medical News article discusses a new finding that healthy infants have high blood levels of the protein p-tau217, a key biomarker for Alzheimer disease.

A recent study showed that newborns have high levels of p-tau, a biomarker for #Alzheimer disease.

Understanding how infants clear the protein could help prevent aggregation, which leads to #neurodegeneration in adults.

Hypoxia ameliorates neurodegeneration and movement disorder in a mouse model of Parkinson’s disease - Nature Neuroscience Parkinson’s disease (PD) involves toxic protein buildup and energy failure in neurons. Continuously breathing low-oxygen air protected mice from PD-like neuronal loss and reversed symptoms, even after...

Hypoxia ameliorates neurodegeneration and movement disorder in a mouse model of Parkinson’s disease

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CHIP protects lysosomes from CLN4 mutant-induced membrane damage Nature Cell Biology - Lee et al. use an aggregation-prone CLN4 mutant that causes lysosomal damage in neurons and show that in non-neurons, the ubiquitin ligase CHIP prevents CLN4-dependent...

Happy to share an exciting study from Yihong Ye’s lab at NIH, with a minor contribution from our lab: ceroid lipofuscinosis-4 (CLN4)-linked DNAJC5 mutations cause lysosomal damage as a driver of neurodegeneration in iPSC-derived neurons. CHIP safeguards lysosomes via microautophagy 👉 rdcu.be/eChof

Neurons and astrocytes have distinct organelle signatures and responses to stress Neurons and astrocytes play critical yet divergent roles in brain physiology and neurological conditions. Intracellular organelles are integral to cel…

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Microglia transcriptional states and their functional significance: Context drives diversity In the brain, microglia are continuously exposed to a dynamic microenvironment throughout life, requiring them to adapt accordingly to specific develo…

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TDP-43 seeding induces cytoplasmic aggregation heterogeneity and nuclear loss of function of TDP-43 Rummens et al. demonstrate that amyloid-like fibrils trigger TDP-43 aggregation and nuclear depletion, key hallmarks of neurodegenerative disorders. This provokes a unique transcriptomic signature wit...

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AAV vectors trigger DNA damage response-dependent pro-inflammatory signalling in human iPSC-derived CNS models and mouse brain - Nature Communications Costa-Verdera et. al describe a mechanism by which AAV vector genomes activate P53-mediated signalling in CNS cells involving downstream STING activation and pro-inflammatory responses. Inhibition of ...

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Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects ALS-FTD–associated TDP-43 point mutation in endothelial cells leads to BBB loss and is replicated by gene deletion.

www.science.org/doi/10.1126/...

Prevention of Transgene Silencing During Human Pluripotent Stem Cell Differentiation While high and stable transgene expression can be achieved in undifferentiated pluripotent stem cells, conventional transgene expression systems are often silenced upon differentiation. Silencing occu...

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Secreted neurofilament light chain after neuronal damage induces myeloid cell activation and neuroinflammation Neurofilament light chain (NfL) is a neuron-specific cytoskeletal protein that provides structural support for axons and is released into the extracel…

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Proteostasis and lysosomal repair deficits in transdifferentiated neurons of Alzheimer’s disease - Nature Cell Biology Chou et al. generate transdifferentiated human neurons from fibroblasts from young or aged individuals and patients with Alzheimer’s disease. Studies of endolysosomes and proteostasis suggest a role f...

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Single-cell transcriptomic and functional studies identify glial state changes and a role for inflammatory RIPK1 signaling in ALS pathogenesis How glial cells change and impact ALS pathogenesis is unclear. Zelic et al. utilize single-nucleus RNA sequencing to identify disease-enriched glial inflammatory states and activation markers in ALS s...

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A human brain map of mitochondrial respiratory capacity and diversity - Nature The ability to physically partition the human brain at a spatial resolution comparable to neuroimaging methods enabled the development of a brain-wide atlas of mitochondrial content, specialization an...

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APOE genotype determines cell-type-specific pathological landscape of Alzheimer’s disease Using single-nucleus RNA sequencing on post-mortem brains from control subjects and Alzheimer’s disease patients, Li et al. revealed APOE-genotype-specific molecular alterations across distinct brain ...

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The end of the genetic paradigm of cancer Genome sequencing results and single-cell transcriptomics continue to produce findings that challenge the idea that cancer is purely a ‘genetic disease’. This Essay delves into cancer omics data that ...

Maverick.

Multi-cohort cerebrospinal fluid proteomics identifies robust molecular signatures across the Alzheimer disease continuum Ali et al. investigate proteomic changes in cerebrospinal fluid across multiple Alzheimer’s disease cohorts. They identify 2,029 dysregulated proteins that cluster into four groups, enriched in differ...

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Mitochondrial respiratory complex IV deficiency recapitulates amyotrophic lateral sclerosis - Nature Neuroscience Cheng et al. identify a mitochondrial complex IV (CIV) deficiency in the brains of patients with sporadic amyotrophic lateral sclerosis (ALS). They demonstrate that defects in mitochondrial CIV induce...

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Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing - Nature Genetics This isoform-centric microglia genomic atlas includes 35,879 novel human microglia isoforms identified by long-read RNA sequencing. A multi-ancestry quantitative trait locus meta-analysis of known and...

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Endothelial TDP-43 depletion disrupts core blood–brain barrier pathways in neurodegeneration - Nature Neuroscience Targeting the endothelium across ages and neurodegenerative diseases in 92 donors with single-cell inCITE-seq reveals similar alterations in ~40% of capillaries in AD, ALS and FTD. Endothelial TDP-43 ...

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Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer’s disease - Nature Medicine Spatial transcriptomics reveals distinct microglial mechanisms driving amyloid-β clearance in both passively and actively immunized patients with Alzheimer’s disease.

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Cell2fate infers RNA velocity modules to improve cell fate prediction - Nature Methods Cell2fate improves RNA velocity analysis of single-cell and spatial transcriptomics data by module decomposition of realistic biophysical models of transcription dynamics.

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Circular Vectors as an efficient, fully synthetic, cell-free approach for preparing small circular DNA as a plasmid substitute for guide RNA expression in CRISPR–Cas9 genome editing - Nature Protocols Oliynyk and Church present a protocol for designing, synthesizing and purifying transfection-ready, small, circular, double-stranded DNA templates for expression of gRNAs for different genome-editing ...

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Astrocyte heterogeneity reveals region-specific astrogenesis in the white matter - Nature Neuroscience White matter (WM) astrocytes differ significantly from gray matter astrocytes, with WM astrocytes in the forebrain exhibiting unique proliferation capacity, which is absent in cerebellar WM, suggestin...

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The Gene That Made Mice Squeak Strangely A new study suggests that the NOVA1 gene may have been a key player in the evolution of human language.

Yeeesss, a super cool study that was communicated to the public with appropriate nuance and complexity!!

www.nytimes.com/2025/02/18/s...

The neuroimmune connectome in health and disease - Nature A review of studies on communication between the nervous and immune systems redefines the neuroimmune connectome with a focus on health and disease, and discusses how the latest techniques can advance...

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Bioaccumulation of microplastics in decedent human brains - Nature Medicine Pyrolysis gas chromatography–mass spectrometry reveals the presence of microplastics and nanoplastics in human kidney, liver and brain tissue samples from 2016 and 2024, with higher proportions found ...

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Genomic Foundationless Models: Pretraining Does Not Promise Performance The success of Large Language Models has inspired the development of Genomic Foundation Models (GFMs) through similar pretraining techniques. However, the relationship between pretraining performance ...

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