Compensatory mechanisms in genetic models of neurodegeneration: are the mice better than humans?

Abstract

Neurodegenerative diseases are one of the main causes of mental and physical disabilities. Neurodegeneration has been estimated to begin many years before the first clinical symptoms manifest, and even a prompt diagnosis at this stage provides very little advantage for a more effective treatment as the currently available pharmacotherapies are based on disease symptomatology. The etiology of the majority of neurodegenerative diseases remains unknown, and even for those diseases caused by identified genetic mutations, the direct pathways from gene alteration to final cell death have not yet been fully elucidated. Advancements in genetic engineering have provided many transgenic mice that are used as an alternative to pharmacological models of neurodegenerative diseases. Surprisingly, even the models reiterating the same causative mutations do not fully recapitulate the inevitable neuronal loss, and some fail to even show phenotypic alterations, which suggests the possible existence of compensatory mechanisms. A better evaluation of these mechanisms may not only help us to explain why neurodegenerative diseases are mostly late-onset disorders in humans but may also provide new markers and targets for novel strategies designed to extend neuronal function and survival. The aim of this mini-review is to draw attention to this under-explored field in which investigations may reasonably contribute to unveiling hidden reserves in the organism.

Transgenic Mice Overexpressing Human STIM2 and ORAI1 in Neurons Exhibit Changes in Behavior and Calcium Homeostasis but Show No Signs of Neurodegeneration

“…In contrast to our findings in cultured neurons [2], Ca 2+ imaging that was performed on hippocampal slices isolated from double transgenic STIM2/ORAI1 mice did not reveal significant changes in basal cytosolic Ca 2+ level ( Figure 1C,E). This may result from the differences between biological models that were used in the original and the current study (neuronal cultures [2] vs ex vivo tissue-this study) or from the existence of compensatory mechanisms that are often observed in transgenic animals [46]. Nevertheless, our Ca 2+ imaging experiments showed an altered Ca 2+ response in neurons following a strong physiological stimulus (the application of glutamate).…”

Modeled changes of cerebellar activity in mutant mice are predictive of their learning impairments

“…Given that the brain is highly plastic, especially throughout development, there are multiple compensatory mechanisms, which may help to cope with the loss of a certain gene or protein5051. We show that our model can cope with most of them.…”

Transcriptional signatures of brain aging and Alzheimer’s disease: What are our rodent models telling us?

“…This discordant effect suggests the interesting speculation that some model mice, introduced to a human genetic pathology, may generate an opposing and potentially compensatory response. If so, then some of these opposing changes may represent reasonable therapeutic targets for human studies [40, 41]. The 5xFAD, and CK-p25 mice generally showed better agreement with human AD.…”