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1.
Sci Rep ; 13(1): 13042, 2023 08 10.
Article in English | MEDLINE | ID: mdl-37563224

ABSTRACT

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare neurological disorder caused by the mutations in the DARS2 gene, which encodes the mitochondrial aspartyl-tRNA synthetase. The objective of this study was to understand the impact of DARS2 mutations on cell processes through evaluation of LBSL patient stem cell derived cerebral organoids and neurons. We generated human cerebral organoids (hCOs) from induced pluripotent stem cells (iPSCs) of seven LBSL patients and three healthy controls using an unguided protocol. Single cells from 70-day-old hCOs were subjected to SMART-seq2 sequencing and bioinformatic analysis to acquire high-resolution gene and transcript expression datasets. Global gene expression analysis demonstrated dysregulation of a number of genes involved in mRNA metabolism and splicing processes within LBSL hCOs. Importantly, there were distinct and divergent gene expression profiles based on the nature of the DARS2 mutation. At the transcript level, pervasive differential transcript usage and differential spliced exon events that are involved in protein translation and metabolism were identified in LBSL hCOs. Single-cell analysis of DARS2 (exon 3) showed that some LBSL cells exclusively express transcripts lacking exon 3, indicating that not all LBSL cells can benefit from the "leaky" nature common to splice site mutations. At the gene- and transcript-level, we uncovered that dysregulated RNA splicing, protein translation and metabolism may underlie at least some of the pathophysiological mechanisms in LBSL. To confirm hCO findings, iPSC-derived neurons (iNs) were generated by overexpressing Neurogenin 2 using lentiviral vector to study neuronal growth, splicing of DARS2 exon 3 and DARS2 protein expression. Live cell imaging revealed neuronal growth defects of LBSL iNs, which was consistent with the finding of downregulated expression of genes related to neuronal differentiation in LBSL hCOs. DARS2 protein was downregulated in iNs compared to iPSCs, caused by increased exclusion of exon 3. The scope and complexity of our data imply that DARS2 is potentially involved in transcription regulation beyond its canonical role of aminoacylation. Nevertheless, our work highlights transcript-level dysregulation as a critical, and relatively unexplored, mechanism linking genetic data with neurodegenerative disorders.


Subject(s)
Aspartate-tRNA Ligase , Leukoencephalopathies , Humans , Spinal Cord/metabolism , Aspartate-tRNA Ligase/genetics , Aspartate-tRNA Ligase/metabolism , RNA Splicing , Mutation , Leukoencephalopathies/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism
2.
Adv Drug Deliv Rev ; 148: 60-67, 2019 08.
Article in English | MEDLINE | ID: mdl-31100303

ABSTRACT

The focus of regenerative therapies is to replace or enrich diseased or injured cells and tissue in an attempt to replenish the local environment and function, while slowing or halting further degeneration. Targeting neurological diseases specifically is difficult, due to the complex nature of the central nervous system, including the difficulty of bypassing the brain's natural defense systems. While cell-based regenerative therapies show promise in select tissues, preclinical and clinical studies have been largely unable to transfer these successes to the brain. Advancements in nanotechnologies have provided new methods of central nervous system access, drug and cell delivery, as well as new systems of cell maintenance and support that may bridge the gap between regenerative therapies and the brain. In this review, we discuss current regenerative therapies for neurological diseases, nanotechnology as nanocarriers, and the technical, manufacturing, and regulatory challenges that arise from inception to formulation of nanoparticle-regenerative therapies.


Subject(s)
Nanomedicine , Nanotechnology , Nervous System Diseases/drug therapy , Regenerative Medicine , Animals , Drug Delivery Systems , Humans
3.
Neuroscience ; 302: 165-73, 2015 Aug 27.
Article in English | MEDLINE | ID: mdl-25239371

ABSTRACT

The pervasive reach of the inflammatory system is evidenced by its involvement in numerous disease states. Cardiovascular disease, marked by high levels of circulating inflammatory mediators, affects an estimated 83.6 million Americans. Similarly, human immunodeficiency virus (HIV) produces a paradoxical state of generalized immune activity despite widespread immunosuppression, and affects 35 million people worldwide. Patients living with HIV (PLWH) suffer from inflammatory conditions, including cardiovascular disease (CVD), at a rate exceeding the general population. In this combined disease state, immune mechanisms that are common to both CVD and HIV may interact to generate a progressive condition that contributes to the exacerbated pathogenesis of the other to the net effect of damage to the brain. In this review, we will outline inflammatory cell mediators that promote cardiovascular risk factors and disease initiation and detail how HIV-related proteins may accelerate this process. Finally, we examine the extent to which these comorbid conditions act as parallel, perpendicular, or progressive sequela of events to generate a neurodegenerative environment, and consider potential strategies that can be implemented to reduce the burden of CVD and inflammation in PLWH.


Subject(s)
Cardiovascular Diseases/pathology , HIV Infections/pathology , Inflammation/pathology , Animals , Cardiovascular Diseases/epidemiology , Cytokines/metabolism , Disease Progression , HIV Infections/epidemiology , Humans , Inflammation/epidemiology , Macrophages/metabolism , Macrophages/pathology , Microglia/metabolism , Microglia/pathology , Risk Factors
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