Biology subjects

Bictash, M.

Publications and source records attributed to Bictash, M..

3 recordsLinked to original sources

bioRxiv2024

Identification of novel small molecule chaperone activators for neurodegenerative disease treatment

A pathological hallmark of neurodegenerative disease is the accumulation of aberrant protein aggregates which contribute to the cytotoxicity and are therefore a target for new therapy development. One key machinery to manage cellular protein homeostasis is the chaperones proteins, the heat shock proteins (HSPs) which are known to target aberrant proteins including TDP-43, tau and amyloid and rescue neurodegeneration in various disease models. As an attempt to target HSP activation for neurodegeneration therapy, we develop a drug screening assay to search compounds that activate the master regulator of HSPs, the transcription factor heat shock factor 1 (HSF1). As HSF1 is bound by HSP90 which prevents its activation, we develop a NanoBRET assay, which allows us to monitor and quantify the HSF1-HSP90 interaction in living cells to screen for compounds disrupting this interaction and thereby releasing HSF1 for activation. After the assay was optimised and validated for its robustness and reliability, a two thousand compound library was screened which produced 10 hits including a couple of known HSP90 inhibitors. Follow-up functional study showed that one of the hit oxyphenbutazone (OPB) significantly reduces the accumulation of insoluble TDP-43 in a cell model, displaying no signs of stress or toxicity. Further works are needed to characterise the mode-of-action of OPB in HSF1 activation and aberrant protein reduction, and the physiological impact of OPB on TDP-43 needs to be examined in an in vivo model. However, this study demonstrates a viable strategy for new drug discovery in targeting aberrant proteins and identifies potential candidates for translation into neurodegenerative disease treatment.

molecular biology↗

bioRxiv2020

Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson's disease at Chr16q11.2 and on the MAPT H1 allele.

Parkinsons disease (PD) is a common incurable neurodegenerative disease. The identification of genetic variants via genome-wide association studies (GWAS) has considerably advanced our understanding of the PD genetic risk. Understanding the functional significance of the risk loci is now a critical step towards translating these genetic advances into an enhanced biological understanding of the disease. Impaired mitophagy is a key causative pathway in familial PD, but its relevance to idiopathic PD is unclear. We used a mitophagy screening assay to evaluate the functional significance of risk genes identified through GWAS. We identified two new regulators of PINK1-mitophagy, KAT8 and KANSL1, previously shown to modulate lysine acetylation. We show that KAT8 and KANSL1 modulate PINK1 gene expression and subsequent PINK1-mitophagy. These findings suggest PINK1-mitophagy is a contributing factor to idiopathic PD. KANSL1 is located on chromosome 17q21 where the risk associated gene has long been considered to be MAPT. While our data does not exclude a possible association between the MAPT gene and PD, it provides strong evidence that KANSL1 plays a crucial role in the disease. Finally, these results enrich our understanding of physiological events regulating mitophagy and establish a novel pathway for drug targeting in neurodegeneration.

neuroscience↗

bioRxiv2017

Molecular and functional variation in iPSC-derived sensory neurons

Induced pluripotent stem cells (iPSCs), and cells derived from them, have become key tools to model biological processes and disease mechanisms, particularly in cell types such as neurons that are difficult to access from living donors. Here, we present the first map of regulatory variants in an iPSC-derived cell type. To investigate genetic contributions to human sensory function, we performed 123 differentiations of iPSCs from 103 unique donors to a sensory neuronal fate, and measured gene expression, chromatin accessibility, and neuronal excitability. Compared with primary dorsal root ganglion, where sensory nerves collect near the spinal cord, gene expression was more variable across iPSC-derived neuronal cultures, particularly in genes related to differentiation and nervous system development. Single cell RNA-sequencing revealed that although the majority of cells are neuronal and express the expected marker genes, a substantial fraction have a fibroblast-like expression profile. By applying an allele-specific method we identify 3,778 quantitative trait loci influencing gene expression, 6,318 for chromatin accessibility, and 2,097 for RNA splicing at FDR 10%. A number of these overlap with common disease associations, and suggest candidate causal variants and target genes. These include known causal variants at SNCA for Parkinsons disease and TNFRSF1A for multiple sclerosis, as well as new candidates for migraine, Parkinsons disease, and schizophrenia.

genomics↗