Temporal deregulation of genes and microRNAs in neurons during prion-induced neurodegeneration

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2014-09, 2014-01, 2013-10, 2012-11-08, 2012, 2010-06-18
Majer, Anna
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Virology Journal
Expert Opin Drug Discov
PLoS Pathogens
Brain Research
Prion diseases are fatal and incurable neurodegenerative diseases that share many pathological similarities to other neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease. One of the earliest pathological signs commonly detected in all of these diseases is the dysfunction followed by loss of neuronal synapses, spines and eventually dendrites that collectively contribute to disruption of normal brain function. These pathologies tend to progressively accumulate within the brain tissue such that extensive damage typically precedes clinical symptom manifestation and ultimate death of neurons. Clearly, understanding the molecular processes responsible for these pathologies could uncover critical pathway(s) that are responsible for propagating this brain damage and could therefore be exploited for therapy development. However, molecular mechanisms implicated in this early pathology remain unidentified. To address this gap in knowledge, this thesis describes a transcriptional approach coupled with specific isolation of neuronal-enriched tissue which was used to help delineate cellular pathways involved in prion-induced neurodegeneration. Profiling cell bodies of CA1 hippocampal neurons known to be affected during early prion disease revealed temporal alteration in both gene and microRNA (gene regulators) expression throughout disease. On a gene expression level, changes in transcript expression during preclinical disease were reminiscent of an activity-dependent neuroprotective gene signature previously described in the literature. These neuroprotective genes were induced during preclinical disease, diminished as disease progressed and were abolished at clinical disease. In support of this process, upregulation of the phosphorylated form of the neuroprotective transcription factor CREB was detected during preclinical disease in these neurons. Furthermore, several genes known to be induced by CREB were also upregulated at preclinical disease in prion-infected mice. Interestingly, expression of numerous deregulated microRNAs paralleled the neuroprotective gene signature of which several are known to remodel neuronal spines and dendrites. To determine whether other preclinically induced microRNAs were also capable of remodeling neuronal structures, gain-of-function studies were performed in primary mouse hippocampal neurons for the uncharacterized miR-26a-5p. Neurons over-expressing miR-26a-5p had enhanced spine density and dendrite arborization, similar to other preclinically-induced microRNAs. Together, these data suggests that CA1 hippocampal neurons induce a neuroprotective transcriptional signature that is evident early in the course of disease within CA1 hippocampal neurons and is abolished by clinical disease. Reestablishment of key molecules that can induce this neuroprotective signature at a time when these genes begin to dissipate could prolong prion disease onset and delay clinical symptom manifestation.
prions, microRNA, neurodegeneration, gene expression, neurons, hippocampus, laser capture microdissection, preclinical, clinical, neuroprotection, animal model, NMDAR
Shott RH, Majer A, Frost KL, Booth SA, Schang LM. 2014. Activation of pro-survival CamK4β/CREB and pro-death MST1 signaling at early and late times during a mouse model of prion disease. Virol J. 11:160
Majer A, Booth SA. 2014. Microdissection and transcriptional profiling: a window into the pathobiology of preclinical prion disease. Prion. 8:67-74.
Boese AS, Majer A, Saba R, and Booth SA. 2013. Small RNA drugs for prion disease: a new frontier. Expert Opin Drug Discov. 10:1265-84
Majer A, Medina SJ, Niu Y, Abrenica B, Manguiat KJ, et al. (2012) Early Mechanisms of Pathobiology Are Revealed by Transcriptional Temporal Dynamics in Hippocampal CA1 Neurons of Prion Infected Mice. PLoS Pathog 8(11): e1003002. doi:10.1371/journal.ppat.1003002
Majer A, Boese AS, and Booth SA. 2012. The role of microRNAs in neurodegenerative diseases: Implications for early detection and treatment. In: Mallick B. Regulatory RNAs. Berlin: Heildelberg, Springer
Majer A and Booth SA. 2010. Computational methodologies for studying non-coding RNAs relevant to central nervous system function and dysfunction. Brain Res. 1338:131-45