Altered expression of atypical PKC and Ryk in the spinal cord of a mouse model of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive paralysis due to the selective death of motor neurons of unknown causes. Increasing evidence indicates that Wnt signaling is altered in ALS. In this study, we focused on two non-canonical Wnt signaling components, atypical PKC (aPKC) and a Wnt receptor, Ryk, in a mouse model of ALS, SOD1 (G93A). aPKC mediates Wnt signaling to regulate growth cone guidance, axon differentiation and cell survival. Ryk is a Wnt repulsive receptor that regulates axon guidance and inhibits regeneration after spinal cord injury. aPKC expression was increased in motor neurons of the lumbar spinal cord in SOD1 (G93A) mice at different stages. Interestingly, aPKC was colocalized with SOD1 in motor neuron cell bodies and extracellular aggregates, and aPKC-containing extracellular aggregates increased with disease progression. Biochemical fractionation showed that aPKC protein level was increased in the detergent-insoluble protein fraction in SOD1 (G93A) mice at late stage but decreased in the detergent-soluble fraction at symptomatic stage. These results suggest that aPKC may be sequestered in SOD1 aggregates, impairing its ability to protect motor neurons from death. Ryk expression was also increased in the motor neurons and the white matter in the ventral lumbar spinal cord of mutant SOD1 mice with a peak at early stage. These observations indicate that Wnt/aPKC and Wnt/Ryk signaling are altered in SOD1 (G93A) mice, suggesting that changed Wnt signaling may contribute to neurodegeneration in ALS.

Constitutive downregulation protein kinase C epsilon in hSOD1G93A astrocytes influences mGluR5 signaling and the regulation of glutamate uptake

“…Modification in the expression of several protein kinases and phosphatases in the CNS of hSOD1 G93A animals has already been reported (Hu, Chernoff, Pelech, & Krieger, 2003). An altered expression of atypical PKCs has been observed in the spinal cord of mice harboring the G93A mutation (Tury, Tolentino, & Zou, 2014). In the present study, a considerable down-regulation of PKCE was observed in hSOD1 G93A astrocytes when compared with WT astrocytes.…”

The Extraocular Muscles Are Selectively Spared in ALS

“…Several Wnt proteins, including Wnt1, Wnt3a, Wnt 5a, and Wnt7a, are highly expressed at the neuromuscular junction, in muscle fibers, and in motor neurons, and abnormal Wnt signaling has been reported in ALS and a number of other neuromuscular conditions [41][42][43][44][45][46]. In particular, Wnt1 has been assigned important roles in muscle regeneration and in synaptic plasticity, acting on both sides of the synapse [41,47].…”

Axon guidance and injury — lessons from Wnts and Wnt signaling

“…Therefore, manipulating Wnt signaling may affect myelin repair. In addition to axon regeneration and glial responses, Wnt signaling is likely important in regulating axon survival and/or degeneration, as robust changes of Wnt signaling components in animal models of neurodegeneration have been observed [54]. Therefore, functional improvements may also be contributed by increase of neuronal survival after spinal cord injury, which need to be characterized.…”