We performed transcriptome analysis using RNA sequencing on substantia nigra pars compacta (SNpc) from mice after acute and chronic 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) treatment and Parkinson's disease (PD) patients. Acute and chronic exposure to MPTP resulted in decreased expression of genes involved in sodium channel regulation. However, upregulation of pro-inflammatory pathways was seen after single dose but not after chronic MPTP treatment. Dopamine biosynthesis and synaptic vesicle recycling pathways were downregulated in PD patients and after chronic MPTP treatment in mice. Genes essential for midbrain development and determination of dopaminergic phenotype such as,

Cerebrovascular lesions seen as white matter hyperintensity in MRI of elderly population caused due to micro-infracts and micro-bleeds contributes to vascular dementia. Such vascular insult caused by impairment in blood flow to specific area in brain involving small vessels can gradually worsen the pathology leading to cognitive deficits. In the present study we developed a transient model of vaso-constriction to study the impact of such pathology by bilateral injection of ET-1 (Endothelin-1; a 21 amino acid vasoconstricting peptide) into lateral ventricles of C57 mice. The impediment in cerebral blood flow decreased CD31 expression in endothelial cells lining the blood vessels around the hippocampal region, leading to memory deficits after 7 days. Activity dependent protein translation, critical for synaptic plasticity was absent in synaptoneurosomes prepared from hippocampal tissue. Further, Akt1- mTOR signaling cascade was downregulated indicating the possible cause for loss of activity dependent protein translation. However, these effects were reversed after 30 days indicating the ephemeral nature of deficits following a single vascular insult. Present study demonstrates that vasoconstriction leading to memory deficit and decline in activity dependent protein translation in hippocampus as a potential molecular mechanism impacting synaptic plasticity.

We performed transcriptome analysis using RNAseq on substantia nigra pars compacta (SNpc) from mice after single exposure, 14 days after daily MPTP treatment and Parkinson's disease (PD) patients. Single dose of MPTP resulted in downregulation of genes involved in sodium channel regulation, which was also observed after 14 days. Upregulation of pro-inflammatory pathways was seen after single dose but not after 14 days of MPTP treatment. Dopamine biosynthesis and synaptic vesicle recycling pathways were downregulated both in mice after 14 days of MPTP and PD patients. LMX1B, that is essential for midbrain development and determination of dopaminergic phenotype and other genes including FOXA1, RSPO2, KLHL1, EBF3, PITX3, RGS4, ALDH1A1, RET, FOXA2, EN1, DLK1, GFRA1, LMX1A, NR4A2, GAP43, SNCA, PBX1 and GRB10 were downregulated in human PD. Downregulation of ensemble of genes involved in development and differentiation of dopaminergic neurons indicate their critical involvement in pathogenesis and progression of human PD.

Background Imaging and neuropathological studies have revealed the entorhinal cortex (EC) and hippocampus (HP) circuitry to be affected early on during Alzheimer’s disease (AD) progression. Changes in the EC‐HP circuitry also correlate with the episodic memory deficits that have been reported in AD. Using bulk RNA sequencing, we studied the gene expression changes in the EC and HP of adolescent (1‐month old) and young adult (3‐months old) APPswe/PS1ΔE9 (APP/PS1) mice. The analysis of RNA‐seq data revealed a single common gene, the expression of which was perturbed at both ages and both regions. We further studied the physiological implication of this gene in the transgenic mouse model of AD. Method Total RNA was isolated at 1 month and 3 months of age from the EC and HP of male APP/PS1 transgenic (Tg) and wild type (WT) control mice as an input for Illumina paired end sequencing. The reads were aligned to mouse genome after adapter trimming and read counts were generated and normalized using DESeq2 for differential gene expression analysis. qRT‐PCR based validation was performed for the differentially expressed genes. Over‐expression of novel candidate gene on primary hippocampal cultures from Tg and WT APP/PS1 mice was achieved using lentiviral transduction. Imaging of neurons was performed on Zeiss confocal microscope and morphometry and spine analysis was done using Neurolucida software. Result APP was found to be upregulated in both EC and HP at 1 month and 3 months of age in APP/PS1 mice, which served as a positive control. A single gene was consistently down‐regulated at both 1 and 3 months of age in both EC and HP, which was validated through qRT‐PCR. Over‐expression of this gene using lentiviral transduction on APP/PS1 Tg hippocampal neurons in vitro rescued the loss of dendritic complexity observed in these neurons but not spine loss. Finally, we show the down‐regulation of this gene in prefrontal cortex from human AD autopsy tissue as compared to controls. Conclusion In conclusion, our study identified a novel gene candidate that is involved in loss of dendritic complexity in AD pathogenesis early in the disease.