Pituitary adenylate cyclase-activating polypeptide (
PACAP) is a pleiotropic
peptide with autocrine neuroprotective and paracrine anti-inflammatory properties in various models of acute neuronal damage and
neurodegenerative diseases. Therefore, we examined a possible beneficial role of endogenous
PACAP in the
superoxide dismutase 1, SOD1(G93A), mouse model of
amyotrophic lateral sclerosis (ALS), a lethal
neurodegenerative disease particularly affecting somatomotor neurons. In wild-type mice, somatomotor and visceromotor neurons in brain stem and spinal cord were found to express the
PACAP specific receptor PAC1, but only visceromotor neurons expressed
PACAP as a potential autocrine source of regulation of these receptors. In SOD1(G93A) mice, only a small subset of the surviving somatomotor neurons showed induction of
PACAP mRNA, and somatomotor
neuron degeneration was unchanged in
PACAP-deficient SOD1(G93A) mice. Pre-ganglionic sympathetic visceromotor neurons were found to be resistant in SOD1(G93A) mice, while pre-ganglionic parasympathetic neurons degenerated during ALS
disease progression in this mouse model.
PACAP-deficient SOD1(G93A) mice showed even greater pre-ganglionic parasympathetic neuron loss compared to SOD1(G93A) mice, and additional degeneration of pre-ganglionic sympathetic neurons. Thus, constitutive expression of
PACAP and PAC1 may confer neuroprotection to central visceromotor neurons in SOD1(G93A) mice via autocrine pathways. Regarding the progression of
neuroinflammation, the switch from amoeboid to hypertrophic microglial phenotype observed in SOD1(G93A) mice was absent in
PACAP-deficient SOD1(G93A) mice. Thus, endogenous
PACAP may promote microglial cytodestructive functions thought to drive ALS
disease progression. This hypothesis was consistent with
prolongation of life expectancy and preserved tongue motor function in
PACAP-deficient SOD1(G93A) mice, compared to SOD1(G93A) mice. Given the protective role of
PACAP expression in visceromotor neurons and the opposing effect on microglial function in SOD1(G93A) mice, both
PACAP agonism and antagonism may be promising therapeutic tools for ALS treatment, if stage of
disease progression and targeting the specific auto- and paracrine signaling pathways are carefully considered.