Publications by authors named "Kalicharan Patra"

Apolipoprotein E (APOE) genetic variants are most notably known for their divergent impact on the risk of developing Alzheimer's disease. While APOE genotype has been consistently shown to modulate lipid metabolism in a variety of cellular contexts, the effect of APOE alleles on the lipidome in hepatocytes is unknown. In this study, we investigated the contribution of APOE alleles to lipidomic profiles of donor-derived primary human hepatocytes from 77 subjects.

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Background: Low levels of plasma apolipoprotein E (apoE) and presence of the APOE ε4 allele are associated with an increased risk of Alzheimer's disease (AD). Although the increased risk of AD in APOE ε4-carriers is well-established, the protein levels have received limited attention.

Methods: We here report the total plasma apoE and apoE isoform levels at baseline from a longitudinally (24 months) followed cohort including controls (n = 39), patients with stable amnestic mild cognitive impairment during 24 months follow up (MCI-MCI, n = 30), patients with amnestic MCI (aMCI) that during follow-up were clinically diagnosed with AD with dementia (ADD) (MCI-ADD, n = 28), and patients with AD with dementia (ADD) at baseline (ADD, n = 28).

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Liver-generated plasma apolipoprotein E (apoE) does not enter the brain but nonetheless correlates with Alzheimer's disease (AD) risk and AD biomarker levels. Carriers of APOEε4, the strongest genetic AD risk factor, exhibit lower plasma apoE and altered brain integrity already at mid-life versus non-APOEε4 carriers. Whether altered plasma liver-derived apoE or specifically an APOEε4 liver phenotype promotes neurodegeneration is unknown.

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Background: Frontotemporal dementia (FTD) is a neurodegenerative disease, resulting in progressive problems in language and/or behaviour and is often diagnosed before 65 years of age. Ubiquitin positive protein aggregates in the brain are among the key pathologic hallmarks of frontotemporal lobar degeneration (FTLD) postmortem. The TANK-binding kinase 1 gene (TBK1) is on the list of genes that can contribute to the development of FTD as well as the related neurodegenerative disease amyotrophic lateral sclerosis (ALS).

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We identified an autosomal dominant progranulin mutation carrier without symptoms of dementia in her lifetime (Reduced Penetrance Mutation Carrier, RedPenMC). This resistance to develop expected pathology presents a unique opportunity to interrogate neurodegenerative mechanisms. We performed multimodal single-nuclei analyses of post-mortem frontal cortex from RedPenMC, including transcriptomics and global levels of chromatin marks.

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The aggregation of abnormally phosphorylated tau protein in neurons and glia is a neuropathological hallmark of several neurodegenerative disorders, collectively known as tauopathies. They are further subclassified based on the preferential pathological aggregation of three carboxyl-terminal repeat domains (3R) and/or 4R tau. Corticobasal degeneration (CBD) is a rare neurodegenerative disorder classified as a 4R tauopathy.

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The APOEɛ4 gene variant is the strongest genetic risk factor for Alzheimer's disease (AD), whereas APOEɛ3 conventionally is considered as 'risk neutral' although APOEɛ3-carriers also develop AD. Previous studies have shown that the apolipoprotein E3 (apoE3) isoform occurs as monomers, homodimers and heterodimers with apolipoprotein A-II in human body fluids and brain tissue, but the relevance of a plasma apoE3 monomer/dimer profile to AD is unknown. Here we assessed the distribution of monomers, homodimers and heterodimers in plasma from control subjects and patients with mild cognitive impairment (MCI) and AD with either a homozygous APOEɛ3 (n = 31 control subjects, and n = 14 MCI versus n = 5 AD patients) or APOEɛ4 genotype (n = 1 control subject, n = 21 MCI and n = 7 AD patients).

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Accumulating evidence demonstrating higher cerebrospinal fluid (CSF) α-synuclein (αSyn) levels and αSyn pathology in the brains of Alzheimer's disease (AD) patients suggests that αSyn is involved in the pathophysiology of AD. To investigate whether αSyn could be related to specific aspects of the pathophysiology present in both sporadic and familial disease, we quantified CSF levels of αSyn and assessed links to various disease parameters in a longitudinally followed cohort (n = 136) including patients with sporadic mild cognitive impairment (MCI) and AD, and in a cross-sectional sample from the Dominantly Inherited Alzheimer's Network (n = 142) including participants carrying autosomal dominant AD (ADAD) gene mutations and their non-mutation carrying family members.Our results show that sporadic MCI patients that developed AD over a period of two years exhibited higher baseline αSyn levels (p = 0.

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24S-hydroxycholesterol (24OHC) and Tau are produced in neuronal cells and neurodegeneration leads to increased flux of both of them into cerebrospinal fluid (CSF). In the present study, CSF levels of 24OHC and 27S-hydroxycholesterol (27OHC) along with those of Tau, P-Thr-Tau and Aβ were measured in patients with early Parkinson's disease (PD), Corticobasal syndrome (CBS), Corticobasal Degeneration (CBD), and controls. Using mouse models with increased or no formation of Tau protein and increased production of 24OHC, we have also tested the hypothesis that there is a direct association between neuronal turnover of 24OHC and Tau.

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Background: Kallikrein 6 (KLK6) is known to be an age-related protease expressed at high levels in the central nervous system. It was previously shown to be involved in proteolysis of extracellular proteins implicated in neurodegenerative diseases such as Alzheimer's disease (AD), prompting validation of KLK6 as a potential biomarker of disease. However, analyses of both plasma and cerebrospinal fluid (CSF) levels of KLK6 in patients with AD have been inconclusive.

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The striatum serves as the main input to the basal ganglia, and is key for the regulation of motor behaviors, compulsion, addiction, and various cognitive and emotional states. Its deterioration is associated with degenerative disorders such as Huntington's disease. Despite its apparent anatomical uniformity, it consists of intermingled cell populations, which have precluded straightforward anatomical sub-classifications adhering to functional dissections.

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The solute carrier and presynaptic vesicle protein solute carrier family 10 member 4, or vesicular aminergic-associated transporter (VAAT), was recently proven to have a modulatory role in central cholinergic signalling. It is currently unknown whether VAAT also affects peripheral cholinergic synapses. Here we demonstrated a regulatory role for the presynaptic vesicle protein VAAT in neuromuscular junction (NMJ) development and function.

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Background: The neuromodulatory transmitters, biogenic amines, have profound effects on multiple neurons and are essential for normal behavior and mental health. Here we report that the orphan transporter SLC10A4, which in the brain is exclusively expressed in presynaptic vesicles of monoaminergic and cholinergic neurons, has a regulatory role in dopamine homeostasis.

Methods: We used a combination of molecular and behavioral analyses, pharmacology, and in vivo amperometry to assess the role of SLC10A4 in dopamine-regulated behaviors.

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Motor neurons become hyperexcitable during progression of amyotrophic lateral sclerosis (ALS). This abnormal firing behavior has been explained by changes in their membrane properties, but more recently it has been suggested that changes in premotor circuits may also contribute to this abnormal activity. The specific circuits that may be altered during development of ALS have not been investigated.

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The vast diversity of GABAergic interneurons is believed to endow hippocampal microcircuits with the required flexibility for memory encoding and retrieval. However, dissection of the functional roles of defined interneuron types has been hampered by the lack of cell-specific tools. We identified a precise molecular marker for a population of hippocampal GABAergic interneurons known as oriens lacunosum-moleculare (OLM) cells.

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We investigated the role of the axon guidance molecule EphA4 following traumatic brain injury (TBI) in mice. Neutralization of EphA4 improved motor function and axonal regeneration following experimental spinal cord injury (SCI). We hypothesized that genetic absence of EphA4 could improve functional and histological outcome following TBI.

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Article Synopsis
  • Locomotion in mammals is controlled by spinal interneurons that help coordinate limb movements, allowing for smooth and rhythmic motions.
  • A mutation in the DMRT3 gene significantly impacts horse locomotion, enabling diverse gaits and improving performance in harness racing.
  • Research on mice shows that DMRT3 is essential for developing spinal networks that coordinate limb movements, highlighting its critical role in the evolution of gait in various horse breeds.
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Proline rich 15 (Prr15), which encodes a protein of unknown function, is expressed almost exclusively in postmitotic cells both during fetal development and in adult tissues, such as the intestinal epithelium and the testis. To determine if this specific expression is lost in intestinal neoplasias, we examined Prr15 expression by in situ hybridization (ISH) on mouse intestinal tumors caused by different gene mutations, and on human colorectal cancer (CRC) samples. Prr15/PRR15 expression was consistently observed in mouse gastrointestinal (GI) tumors caused by mutations in the Apc gene, as well as in several advanced stage human CRCs.

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Background: The forkhead box/winged helix family members FOXA1, FOXA2, and FOXA3 are of high importance in development and specification of the hepatic linage and the continued expression of liver-specific genes.

Results: Here, we present a genome-wide location analysis of FOXA1 and FOXA3 binding sites in HepG2 cells through chromatin immunoprecipitation with detection by sequencing (ChIP-seq) studies and compare these with our previous results on FOXA2. We found that these factors often bind close to each other in different combinations and consecutive immunoprecipitation of chromatin for one and then a second factor (ChIP-reChIP) shows that this occurs in the same cell and on the same DNA molecule, suggestive of molecular interactions.

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Gene expression is regulated by combinations of transcription factors, which can be mapped to regulatory elements on a genome-wide scale using ChIP experiments. In a previous ChIP-chip study of USF1 and USF2 we found evidence also of binding of GABP, FOXA2 and HNF4a within the enriched regions. Here, we have applied ChIP-seq for these transcription factors and identified 3064 peaks of enrichment for GABP, 7266 for FOXA2 and 18783 for HNF4a.

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