The role of eIF2α phosphatase GADD34 in protein mis folding neurodegeneration

The unfolded protein response (UPR) is a key pathway in protein mis-folding neurodegenerative diseases such as Alzheimer’s, Huntington’s, Parkinson’s and the less common prion diseases. Under normal physiological conditions, the PERK/eIF2α arm of the UPR helps maintain protein homeostasis in response to ER stress through regulation of protein synthesis rates at the level of translation initiation. Phosphorylation of eIF2α deprives cells of ternary complex causing induction of ATF4 and CHOP, transcription factors that regulate a vast array of processes in response to cell stress. A target common to both ATF4 and CHOP is GADD34, an eIF2α phosphatase that downregulates the PERK/eIF2α branch of the UPR as part of a feedback loop. However, despite chronic activation of PERK branch UPR signalling in prion disease and associated detrimental sustained decline in protein synthesis rates, GADD34 is not induced.Investigation of the failure of GADD34 induction in two mouse models of neurodegeneration revealed that GADD34 regulatory elements are functional, but transcriptional induction of ATF4-regulated proteins GADD34, CHOP and ATG12 does not occur. This indicates that there is a non-specific failure of GADD34 induction that results from a generalised failure or downregulation of ATF4 signalling during these protein mis-folding neurodegenerative diseases.Lentivirally-mediated over-expression of ΔhuGADD34 in neurons during prion disease completely restores protein synthesis rates, leading to neuroprotection. A transgenic mouse model capable of inducible expression of ΔhuGADD34 was generated to study its effect in different brain cell populations. Induction throughout the forebrain during prion disease decreased eIF2α-P, however; the resultant 35% increase in protein synthesis was insufficient to be neuroprotective.Accumulation of mis-folded proteins has been observed in various types of brain cell across multiple protein mis-folding neurodegenerative disorders. Preliminary data suggests that targeting the UPR in astrocytes during murine prion disease through lentivirally-mediated over-expression of ΔhuGADD34 under the regulation of a GFAP iipromoter delayed emergence of behavioural deficits, increased survival duration, and prevented neuronal loss. Surprisingly, the extent of protection was equivalent to neuronal expression of ΔhuGADD34. These results suggest that the detrimental effects of UPR activation during disease may not be limited to neuronal populations, but rather dysregulated UPR signalling may act non-cell autonomously.