Table 1. Pharmacological and genetic interventions in death signalling pathways in the nervous system in vivo.

The Table summarizes recent in vivo studies targeting the nervous system, grouping them by target — ligand, receptor or effector — and by the pathology that they most closely model. Genetic gain- or loss-of-function or pharmacological approaches have provided important validation (or invalidation) of mechanisms identified in vitro, and can also serve as proof-of-principle for subsequent therapeutic strategies. The principal outcomes of these interventions are described in the text. Abbreviations: MPTP (1-methyl-4-phenylpyridinium), SNA (sciatic nerve avulsion), (MCAO (middle cerebral artery occlusion), lpr (lymphoproliferative), gld (generalized lymphoproliferative disease), JEV (Japanese Encephalitis Virus).

	Molecule/Gene	Pathology	Model	Approach	Delivery	Reference
Ligand
TNFa	TNFa	ALS	SOD1 G93A, G37R mice	gene KO		[26•]
	TNFa	Parkinson	MPTP neurotoxicity	gene KO		[50]
	TNFa	synaptic scaling	Neuroplasticity	gene KO		[18,19]
	TNFa binding protein	ALS	wobbler mice	recombinant protein	subcutaneous	[27]
TNFa and FasL	Thalidomide, lenalidomide	ALS	SOD1 G93A mice	pharmacological	oral	[29•]
	MMP-9	ALS	SOD1 G93A mice	gene KO		[37,43]
TNFa & IFNγ	IFNγ receptor type 1	Alzheimer	APP mice	gene KO		[44]
FasL	FasL	ALS	SOD1 G93A mice	gld mutation		[40]
	FasL	motor neuron injury	SNA	gld mutation		[46]
	FasL	branching	Neural development	gld and lpr mutations		[17•]
	TIMP-3	stroke	MCAO	gene KO		[15]
	soluble Fas receptor	spinal cord injury		recombinant protein	intrathecal	[45]
Receptor complex
TNFR	TNFR1/2	Parkinson	MPTP neurotoxicity	gene KO		[56]
	TNFR1/2	neuronal injury	Trimethyltin	gene KO		[55•]
	TRADD siRNA	Encephalitis	JEV virus	gene silencing	intracerebral	[13]
Fas	Fas siRNA	ALS	SOD1 G93A mice	gene silencing	intrathecal	[36•]
	FLIP(L)	stroke	MCAO	transgenic expression		[47]
	Fas	motor neuron injury	Axotomy	lpr mutation		[16]
	Fas	Parkinson	MPTP neurotoxicity	lpr and gld mutations		[49]
FADD?	Lithium	ALS	SOD1 G93A mice, human patients	pharmacological	oral, intraperitoneal	[39•,41•]
p75NTR	p75NTR	Alzheimer	Aβ neurotoxicity	gene KO		[12].
Effector
DAXX	Daxx dominant negative	ALS	SOD1 G93A mice	transgenic expression		[9, 10]
NO synthase	nNOS, iNOS	motor neuron injury	SNA	gene KO		[46]
Free radicals	Neu2000	ALS	SOD1 G93A mice	pharmacological	oral	[39•]