Investigating the potential of enhanced neuroprotection through unfolded protein response inhibition and autophagy induction in neurodegeneration
Neurodegenerative diseases pose an immense challenge to the population and health care worldwide. There is a growing need for therapeutic strategies to target these diseases. Many neurodegenerative diseases are classified as protein misfolding diseases (PMDs). Despite their uniqueness, these PMDs share common pathways connected to their pathophysiology. Preclinical evidence demonstrates that these can be manipulated for new disease-modifying drug therapies. The unfolded protein response (UPR) and autophagy are two such pathways, whose dysregulation is detectable as pathological hallmarks in various neurodegenerative diseases. The modulation of both pathways individually is neuroprotective in multiple mouse models of neurodegenerative disease. Evidence from other fields of biomedical research showed the enormous potential benefit of combination therapy in various human diseases. Therefore, this project aimed at investigating the strategy of combination therapy in neurodegeneration by targeting more than one common pathway compared to targeting each one singly. Here fore, two distinct models of neurodegeneration, prion disease and the tauopathy model, rTg4510, were used. It was confirmed that both common pathways, the UPR and autophagy, are implicated in the disease progression. Furthermore, targeting of either pathway, genetically or pharmacologically, demonstrated profound neuroprotection in the hippocampus of both mouse models and extended survival of prion-diseased mice significantly. However, neither genetic nor pharmacological combination therapy showed additive benefit when given early in the disease. When starting genetic or pharmacological treatment in a later phase of disease progression, combination therapy caused an extension of lifespan in prion-diseased mice beyond the effects of monotherapy alone. These results show that the modulation of autophagy genetically and pharmacologically is neuroprotective in prion-diseased mice to a similar extent to PERK pathway modulation. The combinatorial approach did not increase lifespan over monotherapy either genetically or pharmacologically, except when used later in the disease. The reasons for this remain to be explored, but the potential of targeting several processes is an appealing potential strategy in neurodegeneration.
Unfolded Protein Response, Autophagy, Neurodegeneration
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