Biology subjects

Chandrasekaran, G.

Publications and source records attributed to Chandrasekaran, G..

4 recordsLinked to original sources

bioRxiv2024

α-Synuclein Conformations in Plasma Distinguish Parkinson's Disease from Dementia with Lewy Bodies

AbstractSpread and aggregation of misfolded -synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinsons disease (PD) and dementia with Lewy bodies (DLB). While evidence exists for multiple aSyn protein conformations, often termed "strains" for their distinct biological properties, it is unclear whether PD and DLB result from aSyn strain differences, and biomarkers that differentiate PD and DLB are lacking. Moreover, while pathological forms of aSyn have been detected outside the brain (e.g., in skin, gut, blood), the functional significance of these peripheral aSyn species is unclear. Here, we developed assays using monoclonal antibodies selective for two different aSyn species generated in vitro - termed Strain A and Strain B - and used them to evaluate human brain tissue, cerebrospinal fluid (CSF), and plasma, through immunohistochemistry, enzyme-linked immunoassay, and immunoblotting. Surprisingly, we found that plasma aSyn species detected by these antibodies differentiated individuals with PD vs. DLB in a discovery cohort (UPenn, n=235, AUC 0.83) and a multi-site replication cohort (Parkinsons Disease Biomarker Program, or PDBP, n=200, AUC 0.72). aSyn plasma species detected by the Strain A antibody also predicted rate of cognitive decline in PD. We found no evidence for aSyn strains in CSF, and ability to template aSyn fibrillization differed for species isolated from plasma vs. brain, and in PD vs. DLB. Taken together, our findings suggest that aSyn conformational differences may impact clinical presentation and cortical spread of pathological aSyn. Moreover, the enrichment of these aSyn strains in plasma implicates a non-central nervous system source.

neuroscience↗

bioRxiv2021

More than a feeling: scalp EEG and eye correlates of conscious tactile perception

Understanding the neural basis of consciousness is a fundamental goal of neuroscience. Many of the studies tackling this question have focused on conscious perception, but these studies have been largely vision-centric, with very few involving tactile perception. Therefore, we developed a novel tactile threshold perception task, which we used in conjunction with high-density scalp electroencephalography and eye-metric recordings. Participants were delivered threshold-level vibrations to one of the four non-thumb fingers, and were asked to report their perception using a response box. With false discovery rate (FDR) mass univariate analysis procedures, we found significant event-related potentials (ERP) including bilateral N140 and P300 for perceived vibrations; significant bilateral P100 and P300 were found following vibrations that were not perceived. Significant differences between perceived and not perceived trials were found bilaterally in the N140 and P300. Additionally, we found that pupil diameter and blink rate increased and that microsaccade rate decreased following vibrations that were perceived relative to those that were not perceived. While many of the signals are consistent with similar ERP-findings across sensory modalities, our results indicating a significant P300 in not perceived trials raise more questions regarding P300s perceptual meaning. Additionally, our findings support the use of eye metrics as a measure of physiological arousal as pertains to conscious perception, and may represent a novel path toward the creation of tactile no-report tasks in the future. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/466706v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@e4e7fforg.highwire.dtl.DTLVardef@3b3ed0org.highwire.dtl.DTLVardef@198d517org.highwire.dtl.DTLVardef@cddef3_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIA novel tactile perceptual threshold task yields robust behavioral results C_LIO_LIEvent-related potentials differ according to perception status C_LIO_LIP300 is observed in both perceived and not perceived trials C_LIO_LIBlink rate, pupil diameter, and microsaccades differ across trial conditions C_LI

neuroscience↗

bioRxiv2021

A novel mouse model of focal limbic seizures that reproduces behavioral impairment associated with cortical slow wave activity

Patients with focal temporal lobe seizures often experience loss of consciousness. In humans, this loss of consciousness has been shown to be positively correlated with EEG neocortical slow waves, similar to those seen in non-REM sleep. Previous work in rat models of temporal lobe seizures suggests that decreased activity of subcortical arousal systems cause depressed cortical function during seizures. However, these studies were performed under light anesthesia, making it impossible to correlate behavior, and therefore consciousness, to electrophysiologic data. Further, the genetic and molecular toolkits allowing for precise study of the underlying neural circuitry are much more developed in mice than in rats. Here, we describe an awake-behaving, head-fixed mouse model of temporal lobe seizures with both spared and impaired behavior reflecting level of consciousness. Water-restricted mice were head-fixed on a running wheel and trained to associate an auditory stimulus to the delivery of a drop of water from a dispenser. To investigate the effect of seizures on behavior, seizures were electrically induced by stimulating either the left or right hippocampus via a chronically-implanted electrode, while mice were performing the task. Behavior was measured by monitoring lick responses to the auditory stimulus and running speed on the wheel. Further, local field potentials (LFP) signals were simultaneously recorded from hippocampus and orbitofrontal cortex (OFC). Induced focal seizures were 5-30s in duration, and repeatable for several weeks (n=20 animals). Behavioral responses showed a decrease in lick rate to auditory stimulus, and decreased running speed during seizures (p<0.01, n=20 animals). Interestingly, licking response to sound could vary from being impaired to normal during seizures. We found that behavioral impairment is correlated with large amplitude cortical slow-wave activity in frontal cortex, as seen in patients with temporal lobe seizures. These results suggest that induced focal limbic seizures in the mouse can impair consciousness and that the impaired consciousness is correlated with depressed cortical function resembling slow wave sleep. This novel mouse model has similar characteristics with previously studied rat models and human temporal lobe seizures. By leveraging the genetic and molecular techniques available in the mouse, this model can be used to further uncover fundamental mechanisms for loss of consciousness in focal seizures.

neuroscience↗

bioRxiv2019

A genome-wide enrichment screen identifies NUMA1-loss as a resistance mechanism against mitotic cell-death induced by BMI1 inhibition

BMI1 is a core protein of the polycomb repressive complex 1 (PRC1) that is overexpressed in several cancer types, making it a promising target for cancer therapies. However, the underlying mechanisms and interactions associated with BMI1-induced tumorigenesis are often context-dependent and complex. Here, we performed a drug resistance screen on mutagenized human haploid HAP1 cells treated with the BMI1 inhibitor PTC-318 to find new genetic and mechanistic features associated with BMI1-dependent cancer cell proliferation. Our screen identified NUMA1-mutations as the most significant inducer of PTC-318 cell death resistance. Independent validations on NUMA1-proficient HAP1 and non-small cell lung cancer cell lines exposed to BMI1 inhibition by PTC-318 or BMI1 knockdown resulted in cell death following mitotic arrest. Interestingly, cells with CRISPR-Cas9 derived NUMA1 knockout also showed a mitotic arrest phenotype following BMI1 inhibition but, contrary to cells with wildtype NUMA1, these cells were resistant to BMI1-dependent cell death. The current study brings new insights to BMI1 inhibition-induced mitotic lethality in cancer cells and presents a previously unknown role for NUMA1 in this process.

cancer biology↗