Integrated analysis of genetic, behavioral, and biochemical data implicates neural stem cell-induced changes in immunity, neurotransmission and mitochondrial function in Dementia with Lewy Body mice

Abstract

We previously demonstrated that transplantation of murine neural stem cells (NSCs) can improve motor and cognitive function in a transgenic model of Dementia with Lewy Bodies (DLB). These benefits occurred without changes in human α-synuclein pathology and were mediated in part by stem cell-induced elevation of brain–derived neurotrophic factor (BDNF). However, instrastriatal NSC transplantation likely alters the brain microenvironment via multiple mechanisms that may synergize to promote cognitive and motor recovery. The underlying neurobiology that mediates such restoration no doubt involves numerous genes acting in concert to modulate signaling within and between host brain cells and transplanted NSCs. In order to identify functionally connected gene networks and additional mechanisms that may contribute to stem cell-induced benefits, we performed weighted gene co-expression network analysis (WGCNA) on striatal tissue isolated from NSC- and vehicle-injected wild-type and DLB mice. Combining continuous behavioral and biochemical data with genome wide expression via network analysis proved to be a powerful approach; revealing significant alterations in immune response, neurotransmission, and mitochondria function. Taken together, these data shed further light on the gene network and biological processes that underlie the therapeutic effects of NSC transplantation on α-synuclein induced cognitive and motor impairments, thereby highlighting additional therapeutic targets for synucleinopathies.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0421-0) contains supplementary material, which is available to authorized users.

Deletion of the Capn1 Gene Results in Alterations in Signaling Pathways Related to Alzheimer’s Disease, Protein Quality Control and Synaptic Plasticity in Mouse Brain

“…In order to identify potential cell specific expression of some of the DEGs, we mapped the DEGs to the currently available dataset provided by the Dougherty lab, using the pSI identification method (Dougherty et al, 2010;Xu et al, 2014;Lakatos et al, 2017) 3 . We applied the CSEA to the 354 DEGs and selected the gene list provided for mice.…”

Brain region-dependent gene networks associated with selective breeding for increased voluntary wheel-running behavior

“…Genes associated with reward-dependent behaviors and locomotor control were among those exhibiting highly significant interaction effects and opposite line patterns between the two brain regions ( Table 1 ). Keratin, type I cytoskeletal 25 (Krt25) was over-expressed in Hi relative to Co mice in the Ce and under-expressed in the St. Krt25 was identified as a hub gene in a network of genes associated with Rotarod and Beam Transversal tasks used to assess motor coordination in mice [ 50 ], supporting the observed over-expression in the Ce of Hi relative to Co. Reciprocally, homeobox-containing transcription factor engrailed 2 (En2), laminin subunit gamma-2 (Lamc2), and myosin XVIIIb (Myo18b) were all under-expressed in Hi relative to Co mice in the Ce while over-expressed in the St. In agreement with the profiles detected in this study, En2 knockout mice exhibited deficits in specific motor, spatial learning and memory tasks, and altered social behavior including decreased play, reduced social sniffing and allogrooming, and less aggressive behavior [ 51 ].…”

Neural Stem Cell Therapies: Promising Treatments for Neurodegenerative Diseases

“…In conclusion, neural stem cell therapy holds tremendous promise in the treatment of neurodegenerative diseases such as LBD and CJD. While challenges and limitations exist, the potential benefits of this therapy offer hope for providing a new way to treat and even cure these debilitating conditions (129). Further research is needed to better understand the mechanisms of action and long-term effects; however, the initial results are very encouraging (130) (131).…”