Role of the Akt/GSK-3β/CRMP-2 pathway in axon degeneration of dopaminergic neurons resulting from MPP+ toxicity

Abstract

Parkinson׳s disease (PD) is the most common neurodegenerative disease of the basal ganglia. Earlier reports suggest that the main pathological change in PD is due to apoptosis of dopaminergic neuronal soma in the substantia nigra (SN). The therapies for PD are also largely focused on the prevention of degeneration of the neuronal soma. However, these treatments can only provide temporary relief by delaying the progression of the disease and are therefore unable to prevent the long term neurodegeneration process. This limitation of the existing therapeutic treatment indicates that there may be other causes that either occur earlier or are independent of apoptosis of neuronal soma. Previous studies have shown that axon degeneration may play an important role in PD, and that this may occur at an early stage of the disease. Thus, preventing axon degeneration may be a potential new approach for therapeutic treatment for PD and future therapies can be useful if emphasis is given on the mechanisms of axon degeneration. It has been recognized that microtubule disassembly leads to axon degeneration because the depolymerized microtubules are more likely to be degraded. Previous studies have shown that glycogen synthase kinase-3β (GSK-3β)/collapsin response mediator protein 2 (CRMP-2) signaling pathway could be regulated by Akt for axonal-dendritic polarity. CRMP-2 is critical for specifying axon/dendrite fate possibly by promoting neurite elongation via microtubule assembly. However, whether Akt could regulate GSK-3β/CRMP-2 pathway and the possible effects of this regulation is unclear in dopaminergic axon degeneration induced by 1-methyl-4-phenylpyridiniumion (MPP+). In this study, we observe the degeneration of axon and neuronal soma by scanning electron microscope and tyrosine hydroxylase staining (TH) using a PD model in dopaminergic neurons in vitro. In addition to this, we detect the expression of total and phosphorylated form of Akt, GSK-3β and CRMP-2, as well as the axonal injury marker amyloid precursor protein (APP). From our studies, we observe that axon degeneration is a characteristic feature in the cascade of events that follow when neurons are induced by MPP+. This degeneration process occurs earlier in case of PD and is more severe than the degeneration of the neuronal soma and Akt/ GSK-3β/CRMP-2 pathway is involved in this process.

Keywords: Akt; Axon degeneration; CRMP-2; GSK-3β; Parkinson׳s disease; Pathogenesis.