Table 1.

Transgenic animal models for neuroserpin

Model organism	Genetic modification	Phenotype	References
C. elegans	Overexpression of wild type and H302R SRP-2	Formation of high molecular weight protein aggregates in H302R SRP-2 worms, phenotype aggravated by genetic deletion of HSF-1 and UPR pathways	Schipanski et al. [69]
D. melanogaster	Overexpression of chicken NS	Developmental defects (larval molting defects) caused by failure to progress through ecdysis resulting in significant increase in both larval and pupal lethality	Osterwalder et al. [157]
	Overexpression of wild type and P1–P1' (Pro–Pro) mutated wild type human NS	Ubiquitous expression of wild type NS was lethal for developing embryos, expression in the retina caused a rough eye phenotype. Phenotype rescued by co-expression of Abeta 1–42 peptide. Non-inhibitory P1–P1’-mutant was viable	Kinghorn et al. [60]
	Overexpression of mutated P1–P1' (Pro–Pro) version of wild type, S49P, S52R, H338R and G392E human NS	Intracellular accumulation of mutant NS in the brain of transgenic flies. Locomotor dysfunction in flies expressing mutant NS	Miranda et al. [66]
D. rerio	NS deficiency (knock-out)	Anxiety-like behaviour and deficits in axogenesis in the absence of locomotor defects	Han et al. [95]
	NS deficiency (knock-out)	Following hypoxic injury, developmental defects, reduced locomotion, neuronal loss, vascular malformation and oxidative stress more severe than in wild type animals	Han et al. [95]
M. musculus	Overexpression of wild type chicken NS	Reduced tPA activity in the brain. Following induction of focal ischemic stroke, smaller infarcts and attenuated microglial activation compared to wild type animals	Cinelli et al. [72]
	Overexpression of wild type chicken NS	Behavioural abnormalities (reduced centre exploration in the open-field test and neophobic response to novel objects)	Madani et al. [84]
	Overexpression of wild type human NS crossed with pmn mice (progressive motor neuronopathy)	Compared to pmn mice, decreased plasminogen activator activity in sciatic nerves and spinal cord, increased lifespan, stabilisation of motor behaviour, increased number of myelinated axons and rescued motoneuron number and size upon NS overexpression	Simonin et al. [158]
	Overexpression of wild type, S49P and S52R human NS	Intraneuronal NS-positive inclusion bodies accumulating in the ER in a mutation, age and dose-dependent manner in S49P and S52R mice, with clinical symptoms of the disease	Galliciotti et al. [108]
	Overexpression of wild type and G392E human NS	Age and dose-dependent accumulation of G392E NS in ER and lysosomes. Mutant mice were more susceptible to kainite-induced seizures	Takasawa et al. [113]
	Overexpression of wild type and S49P human NS	Correlation between mutant NS accumulation and neurodegeneration. Transient induction of the UPR in young mice	Schipanski et al. [69]
	Overexpression of wild type and S49P human NS	Transient inflammatory responses and UPR activation at middle stage of the disease, sequestration of UPR activators GRP78 and GRP94 in NS-positive inclusions	Lopez-Gonzalez et al. [118]
	Overexpression of wild type and S49P human NS	Increased expression of the postsynaptic protein PSD-95 in the hippocampus of S49P NS mice	Ingwersen et al. [159]
	NS deficiency (knock-out)	Unaltered tPA activity and behavioural abnormalities: reduced locomotor activity in novel environments, anxiety-like response on the O-maze, neophobic phenotype in the novel object test	Madani et al. [84]
	NS deficiency (knock-out) crossed with human APP-J20 transgenic mice	Rapid clearance of Abeta 1–42 injected into the frontal cortex in the absence of NS. Following crossing with human APP-J20 transgenic mice, decrease in amyloid-beta peptides, reduction in number and size of plaques, increased activity of tPA associated with plaques, rescue of spatial memory defects compared to J20 mice	Fabbro et al. [135]
	NS deficiency (knock-out)	Following induction of focal ischemic stroke, aggravated infarct size and neurological outcome and increased activation of proinflammatory microglia	Gelderblom et al., 2013 [123]
	NS deficiency (knock-out) and NS/tPA double deficient mice	Following kainic acid injection into the amygdala, reduced latency to seizure onset and generalisation, shorter mean time of survival and increase in blood–brain barrier permeability compared to wild type mice. NS/tPA double deficiency led to delayed latency to seizure onset and generalisation and protection from seizure-induced death	Fredriksson et al. [80]
	NS deficiency (knock-out)	In the hippocampus, decreased spine-synapse density, increased expression of the postsynaptic protein PSD-95, decreased synaptic potentiation and behavioural alterations in water maze test, contextual fear conditioning test and in social behaviour	Reumann et al. [97]
	NS deficiency (knock-out)	Deficits in developmental neurogenesis in the hippocampus (reduced proliferation of neuronal precursor cells and premature neuronal differentiation). Altered morphology of dendritic spines, increased expression and decreased proteolytic processing of the chondroitin sulphate proteoglycan aggrecan	Hermann et al. [17]
	NS deficiency (knock-out)	Unaltered neocortical lamination. Proteolytic processing of Reelin, expression of PAI-1, perineuronal net composition and synaptic proteome are unchanged in the neocortex	Kement et al. [18]

The table lists all the studies performed in animal models with modified neuroserpin (NS) expression found in the literature, indicating the species, the genetic modifications performed, the observed phenotypes and the corresponding references