Regulation of SPARC family proteins in disorders of the central nervous system.

Objective

Neuronal loss in the substantia nigra pars compacta (SNpc) in Parkinson's disease (PD) is not uniform as dopamine neurons from the ventral tier are lost more rapidly than those of the dorsal tier. Identifying the intrinsic differences that account for this differential vulnerability may provide a key for developing new treatments for PD.
Method

Here we compared the RNA‐sequenced transcriptomes of ~100 laser captured micro‐dissected SNpc neurons from each tier from seven healthy controls.
Results

Expression levels of dopaminergic markers were similar across the tiers while markers specific to the neighbouring ventral tegmental area were virtually undetected. After accounting for unwanted sources of variation, we identified one hundred and six differentially expressed genes (DEGs) between the SNpc tiers. The genes higher in the dorsal/resistant SNpc tier neurons displayed coordinated patterns of expression across the human brain, their protein products had more interactions than expected by chance and they demonstrated evidence of functional convergence. No significant shared functionality was found for genes higher in the ventral/vulnerable SNpc tier.

Surprisingly but importantly, none of the identified DEGs were among the familial PD genes or genome‐wide associated loci. Finally, we found some DEGs in opposite tier orientation between human and analogous mouse populations.
Interpretation

Our results highlight functional enrichments of vesicular trafficking, ion transport/homeostasis and oxidative stress genes showing higher expression in the resistant neurons of the SNpc dorsal tier. Furthermore, the comparison of gene expression variation in human and mouse SNpc populations strongly argues for the need of human‐focused Omics studies.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ana.25719

Human-Specific Transcriptome of Ventral and Dorsal Midbrain Dopamine Neurons.

Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein involved in the extracellular matrix and interactions between cells during neural development of the central nervous system (CNS). Oxidative glutamate toxicity is involved in CNS diseases, including epilepsy, Alzheimer's disease, and ischemic stroke. However, the molecular mechanism of nerve injury is not fully understood in CNS diseases. Herein, the glutamate-induced nerve damage model was used to explore the molecular mechanisms affecting nerve damage. The levels of SPARC and autophagy were increased in glutamate-induced HT22 hippocampal nerve injury. In summary, the current study confirmed that SPARC regulates autophagy in HT22 hippocampal nerve cells, and its knockdown reduces the glutamate-induced HT22 hippocampal nerve injury by inhibiting autophagy. These findings suggested that SPARC plays a crucial role in nerve injury of CNS diseases.

/pdf/sparc-knockdown-reduces-glutamate-induced-ht22-hippocampal-2yhh3dx1nc.pdf

SPARC Knockdown Reduces Glutamate-Induced HT22 Hippocampal Nerve Cell Damage by Regulating Autophagy.

Long-term exposure to environmental neurotoxic metals is implicated in the induction of dementia and cognitive decline. The present study aims to illustrate the therapeutic role of ipriflavone as a synthetic isoflavone against environmental metal–induced cognitive impairment in rats. Dementia was induced by a mixture of aluminum, cadmium, and fluoride for 90 days followed by ipriflavone for a further 30 days.  Metal-treated animals exhibited abnormal behaviors in the Morris water maze task. Neuropathological biomarkers including oxidative stress (TBARS, NO, SOD, GPX, GST, and GSH), inflammation (TNF- α, IL-6, and IL-1β), neurotransmission (AChE and MAO), and insulin resistance (insulin, insulin receptor, and insulin-degrading enzyme) were altered, which consequently elevated the level of amyloid-β42 and tau protein in the hippocampus tissues inducing neuronal injury. Ipriflavone significantly (P < 0.05) ameliorated the neurobehavioral abnormalities and the cognitive dysfunction biomarkers via antioxidant/anti-inflammatory mechanism. Moreover, ipriflavone downregulated the mRNA expression level of amyloid precursor protein and tau protein, preventing amyloid plaques and neurofibrillary tangle aggregation at P < 0.05. A molecular docking study revealed that ipriflavone has a potent binding affinity towards AChE more than donepezil and acts as a strong AChE inhibitor. Our data concluded that the therapeutic potential of ipriflavone against dementia could provide a new strategy in AD treatment.

Pharmacological implications of ipriflavone against environmental metal-induced neurodegeneration and dementia in rats.

Schizophrenia (SZ) is a devastating neurodevelopmental disease with an accelerated ageing feature. The criteria of metabolic disease firmly fit with those of schizophrenia. Disturbances in energy and mitochondria are at the core of complex pathology. Genetic and environmental interaction creates changes in redox, inflammation, and apoptosis. All the factors behind schizophrenia interact in a cycle where it is difficult to discriminate between the cause and the effect. New technology and advances in the multi-dispensary fields could break this cycle in the future. 

/pdf/schizophrenia-as-metabolic-disease-what-are-the-causes-1ygpl79t.pdf

Schizophrenia as metabolic disease. What are the causes?

Copper (Cu) and Iron (Fe) has been the subject of intensive research over several decades as numerous seminal studies robustly support the involvement of Cu and Fe metabolism dyshomeostasis as a common denominator in several neurodegenerative disorders (particularly Alzheimer’s disease and Parkinson’s disease); however, till date, the exact “cause-effect” association has not been elucidated. Thus, there is urgent need to look for newer association/pathways of these redox active elements in different neuropathological conditions. Therefore, in this study, we have used bioinformatics based approach to identify novel Cu and Fe metabolism proteins in neurodegenerative disorders using Cytoscape software. The network biology data demonstrated the association of secreted protein acidic and rich in cysteine (SPARC/osteonectin) protein with Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and neurodegeneration with brain iron accumulation (NBIA) disease, whereas Coagulation factor V may have a role in Brunner Syndrome, Obsessive-Compulsive Disorder, Febrile seizures and Schizophrenia diseases. Further analysis revealed Coagulation factor VII possible role in L1 Syndrome and Congenital hydrocephalus disorders. In conclusion, the present study shows the first evidence in silico that SPARC/osteonectin, Coagulation factor V and VII proteins may have plausible role in the pathogenesis of various neurodegenerative diseases.

In silico method for identification of novel copper and iron metabolism proteins in various neurodegenerative disorders.

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In silico method for identification of novel copper and iron metabolism proteins in various neurodegenerative disorders.