Biology subjects

Siddique, T.

Publications and source records attributed to Siddique, T..

5 recordsLinked to original sources

bioRxiv2025

Deveolopment of patient-derived neuroprogenitor cells (hNPCs), neurons, and astrocytes to explore the etiology of Guam Parkinsonism-dementia complex (PDC)

Parkinsonism-Dementia Complex (PDC) is one phenotype of a disappearing neurodegenerative disease (Guam ALS-PDC) that shows clinical and neuropathological relationships with amyotrophic lateral sclerosis (ALS), atypical parkinsonism and Alzheimers disease. ALS-PDC has been linked with exposure to environmental factors (notably cycad plant neurotoxins), but evidence from human and animal studies is inconclusive. Patient-derived induced pluripotent stem cells (iPSCs) provide a powerful in vitro system to explore the underlying cause of PDC. iPSC lines were derived from lymphocytes of a PDC-affected Guamanian Chamorro female patient and an age- and gender-matched healthy Chamorro resident of PDC-unaffected Saipan using non-integrating episomal plasmids. iPSCs derived from both patients expressed pluripotency markers (Oct4, SSEA-4, TRA-1-60, Sox2) prior to the generation of neuroprogenitor cells (hNPCs), neurons and astrocytes. An embryoid body protocol was used to derive hNPCs from both iPSC lines while a differentiation media was used to generate neurons from hNPCs. hNPCs derived from both iPSC patients lines displayed established neuroprogenitor markers (nestin, Sox2), while the differentiated hNPCs exhibited both neuronal (beta-tubulin III, Map2, doublecortin) and synaptic (synaptophysin, PSD-95) markers. Expression of these protein markers in hNPCs and neurons by dot blotting was also observed for both lines. Astrocyte progenitor cells and mature astrocytes with appropriate markers were also developed from the hNPCs of both lines using commercial kits. Development of these patient-derived iPSCs provides a human model for evaluating the role of environmental (e.g., cycad toxins) and genetic factors in ALS-PDC and possibly other related neurodegenerative diseases.

neuroscience↗

bioRxiv2023

Exploring the Therapeutic Potential of Cannabis Constituents in Parkinson's Disease: Insights from Molecular Docking Studies

Cannabis, often known as marihuana, marijuana, hashish, and hash, belongs to the genus Cannabis sativa L. This plant has excellent potential for the treatment of several brain disorders. Phytochemical compounds in this plant act as antioxidants, preserving synaptic plasticity and preventing neuronal degeneration. The neurodegenerative condition Parkinsons has emerged as one of the most significant health concerns of the twenty-first century. A detailed in silico molecular docking study was carried out to assess the neuroprotective effects of cannabis compounds against four potential targets of PD, including monoamine oxidase B (MAO-B), catechol-O-methyltransferase (COMT), alpha-synuclein (ASN), and Adenosine A2A receptor (A2A). Physicochemical properties, drug-likeness, toxicity, and ADMET profiles were also investigated. In this docking study, the cannabis compound cannabicyclol showed a superior docking score of -10.8 kcal/mol with the MAO-B protein. Based on these results, cannabicyclol and the target protein MAO-B were used to perform MD simulations to analyze their stability at 100 ns. Furthermore, it is crucial to carry out in vitro and in vivo investigations to enhance the potency of cannabis components and understand the processes underlying the suppression of Parkinsons disease-related enzymes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/566677v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@15f455borg.highwire.dtl.DTLVardef@1c26038org.highwire.dtl.DTLVardef@3b32c6org.highwire.dtl.DTLVardef@82926b_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2022

Hippocampal protein aggregation signatures fully distinguish pathogenic and wildtype UBQLN2 in amyotrophic lateral sclerosis

Mutations in the UBQLN2 gene cause X-linked dominant amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) characterised by ubiquilin 2 aggregates in neurons of the motor cortex, hippocampus, and spinal cord. However, ubiquilin 2 neuropathology is also seen in sporadic and familial ALS or FTD cases not caused by UBQLN2 mutations, particularly C9orf72-linked cases. This makes the mechanistic role of ubiquilin 2 mutations and the value of ubiquilin 2 pathology for predicting genotype unclear. Here we examine a cohort of 41 genotypically diverse ALS cases with or without FTD, including five cases with UBQLN2 variants (resulting in p.S222G, p.P497H, p.P506S, and two cases with p.T487I). Using multiplexed (5-label) fluorescent immunohistochemistry, we mapped the co-localisation of ubiquilin 2 with phosphorylated TDP-43 (pTDP-43), dipeptide repeat aggregates, and p62, in the hippocampus of controls (n=5), or ALS with or without FTD in sporadic (n=20), unknown familial (n=3), SOD1-linked (n=1), FUS-linked (n=1), C9orf72-linked (n=5), and UBQLN2-linked (n=5) cases. We differentiate between i) ubiquilin 2 aggregation together with pTDP-43 or dipeptide repeat proteins, and ii) ubiquilin 2 self-aggregation promoted by UBQLN2 gene mutations that cause ALS/FTD. Overall, we describe a hippocampal protein aggregation signature that fully distinguishes mutant from wildtype ubiquilin 2 in ALS with or without FTD, whereby mutant ubiquilin 2 is more prone than wildtype to aggregate independently of driving factors. This neuropathological signature can be used to assess the pathogenicity of UBQLN2 gene variants and to understand the mechanisms of UBQLN2-linked disease.

neuroscience↗

bioRxiv2019

Nucleocytoplasmic Proteomic Analysis Uncovers ETF1 and Nonsense Mediated Decay as Modifiers of ALS C9orf72 Toxicity

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide repeat expansion in C9orf72 (C9-HRE). While RNA and dipeptide repeats produced by the C9-HRE disrupt nucleocytoplasmic transport, the proteins that become redistributed remain unknown. Here, we utilized subcellular fractionation coupled with tandem mass spectrometry and identified 126 proteins, enriched for protein translation and RNA metabolism pathways, which collectively drive a shift towards a more cytosolic proteome in C9-HRE cells. Amongst these was eRF1, which regulates translation termination and nonsense-mediated decay (NMD). eRF1 accumulates within elaborate nuclear envelope invaginations in patient iPSC-neurons and postmortem tissue and mediates a protective shift from protein translation to NMD-dependent mRNA degradation. Overexpression of eRF1 and the NMD-driver UPF1 ameliorate C9-HRE toxicity in vivo. Our findings provide a resource for proteome-wide nucleocytoplasmic alterations across neurodegeneration-associated repeat expansion mutations and highlight eRF1 and NMD as therapeutic targets in C9orf72-associated ALS/FTD.

neuroscience↗

bioRxiv2017

Identification of TMEM230 mutations in familial Parkinson’s disease (response to comments)

We recently reported mutations in TMEM230 in familial Parkinsons disease (PD). Farrer et al raised the concern that mutations in TMEM230 may not be pathogenic to PD. We seriously evaluated Dr. Farrers assertions. We obtained updated clinical information and performed several new experiments, including MegaEx chip screening of the family DNA samples with [~]2 million SNPs for whole-genome linkage study and re-analysis of whole-exome sequencing data. We did not find any other locus more robust than the chromosome 20p (TMEM230), nor any other variants with better segregation than TMEM230-R141L to explain the inheritance of PD in the large Mennonite family. Based on the new genetic data from the Mennonite PD family, and the robust genetic data showing additional TMEM230 mutations in multiple PD families, we are confident to conclude that TMEM230 is a new PD-causing gene. Further studies of TMEM230 should provide important mechanistic insights into understanding the vesicle/endosome trafficking/recycling defects in the pathogenesis of PD.

genetics↗