Biology subjects

Paliwal, D.

Publications and source records attributed to Paliwal, D..

6 recordsLinked to original sources

bioRxiv2025

Mitochondrial DNA damage in substantia nigra parscompacta astrocytes exacerbates dopaminergic neuron lossin a 6-hydroxydopamine mouse model of parkinsonism

Parkinsons disease (PD) is the fastest growing neurological disorder with no known cure. Our ability to develop disease-modifying treatments that slow down the loss of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons is hindered by a dearth of knowledge on roles for non-neuronal elements such as astrocytes during PD pathogenesis. More specifically, the extent to which mitochondrial DNA (mtDNA) damage in SNc astrocytes contributes to SNc DA neuron loss during PD remains unknown. To address this knowledge gap, we utilized an adeno-associated virus (AAV) called Mito-PstI that expresses the restriction enzyme PstI as an approach to damage mtDNA in SNc astrocytes and assess the effect of astrocytic mtDNA damage on SNc DA neuron function and viability in mice. Mito-PstI-induced mtDNA damage in SNc astrocytes disrupted mitochondrial morphology, caused increased wrapping of SNc astrocytic processes around SNc DA neurons, and abnormally increased dopamine release by SNc DA neuron axonal terminals within the dorsolateral striatum (DLS). In addition, mice injected with Mito-PstI in the SNc showed increased spontaneous and apomorphine-induced rotations contralateral to the side with SNc Mito-PstI injections. In further experiments, we used a parkinsonian mouse model with low dose 6-hydroxydopamine (6-OHDA) injection into the DLS to show that Mito-PstI expression in SNc astrocytes caused a worsening of 6-OHDA-induced spontaneous contralateral rotational behavior, and exacerbated SNc DA neuron loss. These results suggest that mitochondria in SNc astrocytes are not only critical for the function of SNc DA neurons, but are also a new target for developing disease-modifying strategies against PD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/673287v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@b4a98aorg.highwire.dtl.DTLVardef@e6e2fcorg.highwire.dtl.DTLVardef@402b93org.highwire.dtl.DTLVardef@ecdfd2_HPS_FORMAT_FIGEXP M_FIG C_FIG Main PointsO_LIMito-PstI expression in mouse SNc astrocytes increases dopamine release C_LIO_LIMito-PstI expression in SNc astrocytes worsens contralateral rotational behavior in mice C_LIO_LIMito-PstI expression in SNc astrocytes increases DA neuron loss in 6-OHDA mice C_LI

neuroscience↗

bioRxiv2024

NEST: Spatially-mapped cell-cell communication patterns using a deep learning-based attention mechanism

Dysregulation of communication between cells mediates complex diseases such as cancer and diabetes. However, detecting cell-cell communication (CCC) at scale remains one of the greatest challenges in transcriptomics. While gene expression measured with single-cell RNA sequencing and spatial transcriptomics reinvigorated computational approaches to detecting CCC, most existing methods exhibit high false positive rates, do not integrate spatial proximity of ligand-receptor interactions, and cannot detect CCC between individual cells. We overcome these challenges by presenting NEST (NEural network on Spatial Transcriptomics), which uses a graph attention network paired with an unsupervised contrastive learning approach to decipher patterns of communication while retaining the strength of each signal. We introduce new synthetic benchmarking experiments which demonstrate how NEST outperforms existing tools and detects biologically-relevant CCC along with directionality and confidence across spot- and cell-based technologies measuring several different tissues and diseases. In our applications, NEST identifies T-cell homing signals in human lymph nodes, aggressive cancer CCC in lung adenocarcinoma, and discovers new patterns of communication that act as relay networks in pancreatic cancer. Beyond two-dimensional data, we also highlight NESTs ability to detect CCC in three-dimensional spatial transcriptomic data.

bioinformatics↗

bioRxiv2020

Mitochondrial pathway polygenic risk scores are associated with Alzheimer's Disease

INTRODUCTIONGenetic, animal and epidemiological studies involving biomolecular and clinical endophenotypes implicate mitochondrial dysfunction in Alzheimers disease (AD) pathogenesis. Polygenic risk scores (PRS) provide a novel approach to assess biological pathway-associated disease risk by combining the effects of variation at multiple, functionally related genes. METHODSWe investigated associations of PRS for genes involved in 12 mitochondrial pathways (pathway-PRS) related to AD in 854 participants from Alzheimers Disease Neuroimaging Initiative. RESULTSPathway-PRS for four mitochondrial pathways are significantly associated with increased AD risk: (i) response to oxidative stress (OR: 2.01 [95% Cl: 1.71, 2.37]); (ii) mitochondrial transport (OR: 1.81 [95% Cl: 1.55, 2.13]); (iii) hallmark oxidative phosphorylation (OR: 1.23 [95% Cl: 1.07, 1.41]); and (iv) mitochondrial membrane potential regulation (OR: 1.18 [95% Cl: 1.03, 1.36]). DISCUSSIONTherapeutic approaches targeting these pathways may have potential for modifying AD pathogenesis. Further investigation is required to establish a causal role for these pathways in AD pathology.

neuroscience↗

bioRxiv2020

Recombinant SARS-CoV-2 spike proteins for sero-surveillance and epitope mapping

The newly emergent SARS-CoV-2 coronavirus is closely related to SARS-CoV which emerged in 2002. Studies on coronaviruses in general, and SARS in particular, have identified the virus spike protein (S) as being central to virus tropism, to the generation of a protective antibody response and to the unambiguous detection of past infections. As a result of this centrality SARS-CoV-2 S protein has a role in many aspects of research from vaccines to diagnostic tests. We describe a number of recombinant forms of SARS-CoV-2 S expressed in commonly available expression systems and their preliminary use in diagnostics and epitope mapping. These sources may find use in the current and future analysis of the virus and the Covid-19 disease it causes.

microbiology↗

bioRxiv2019

Physical activity improves sarcopenia in a murine model by enhancing the proliferative potential of muscle stem cells, oxidative capacity of mitochondrial enzymes and expression of Sestrins

Sarcopenia is a major health issue in old age. Underlying molecular mechanisms in its genesis remain unclear and optimal animal models are yet to be established. A novel animal model was developed to identify structural and functional changes in skeletal muscles from sarcopenia. The influence of physical activity on animals of the sarcopenic model with respect to the expression of anti-oxidant proteins, mitochondrial oxidative capacity, and effect on muscle stem cells (MuSCs), were assessed. Male C57Bl/6 mice of different age groups were recruited: Y-Cntrl (young-control), A-Cntrl (aged-control), SAR-model and SAR-INT. SAR-model group was kept in a retrofitted confined cage and was fed with customized protein-restricted diet (14% protein), which is considered as a sarcopenic featured model. SAR-INT served as the intervention group. Three parameters, namely, muscle mass, grip strength, and physical endurance, were used to confirm the sarcopenic state. All physical parameters deteriorated most in SAR-model and it improved in the SAR-INT group. The impact of physical activity on the SAR-INT group was also evidenced by the improved proliferative potential of MuSCs determined by flow cytometric analysis. Compared with the SAR-model, the SAR-INT exhibited significant improvement in the oxidative capacity of mitochondrial enzymes and increased expression of anti-oxidant proteins, sestrins. In conclusion, physical activity improved physical parameters, MuSC proliferative potential, mitochondrial enzyme oxidative capacity and sestrin expression in sarcopenic animals. Hence, SAR-model in mice can serve as a novel sarcopenic model, physical activity provides scope for improvement in sarcopenic population and sestrin molecule can have a potential implication on sarcopenia.

molecular biology↗

bioRxiv2019

MitoImpute: A Snakemake pipeline for imputation of mitochondrial genetic variants

BackgroundVariation in mitochondrial DNA (mtDNA) identified by genotyping microarrays or by sequencing only hypervariable regions of the genome may be insufficient to reliably assign mitochondrial genomes to phylogenetic lineages or haplogroups. This lack of resolution can limit functional and clinical interpretation of a substantial body of existing mtDNA data. To address this limitation, we developed and evaluated a method for imputing missing mtDNA single nucleotide variants (mtSNVs) that uses a large reference alignment of complete mtDNA sequences. The method and reference alignment are combined into a pipeline, which we call MitoImpute. ResultsWe aligned the sequences of 36,960 complete human mitochondrial genomes downloaded from GenBank, filtered and controlled for quality. These sequences were reformatted for use in imputation software, IMPUTE2. We assessed the imputation accuracy of MitoImpute by measuring haplogroup and genotype concordance in data from the 1,000 Genomes Project and the Alzheimers Disease Neuroimaging Initiative (ADNI). The mean improvement of haplogroup assignment in the 1,000 Genomes samples was 42.7% (Matthews correlation coefficient = 0.64). In the ADNI cohort, we imputed missing single nucleotide variants. ConclusionsThese results show that our reference alignment and panel can be used to impute missing mtSNVs in exiting data obtained from using microarrays, thereby broadening the scope of functional and clinical investigation of mtDNA. This improvement may be particularly useful in studies where participants have been recruited over time and mtDNA data obtained using different methods, enabling better integration of early data collected using less accurate methods with more recent sequence data.

genomics↗