The Involvement of Polyamines Catabolism in the Crosstalk between Neurons and Astrocytes in Neurodegeneration

Abstract

In mammalian cells, the content of polyamines is tightly regulated. Polyamines, including spermine, spermidine and putrescine, are involved in many cellular processes. Spermine oxidase specifically oxidizes spermine, and its deregulated activity has been reported to be linked to brain pathologies involving neuron damage. Spermine is a neuromodulator of a number of ionotropic glutamate receptors and types of ion channels. In this respect, the Dach-SMOX mouse model overexpressing spermine oxidase in the neocortex neurons was revealed to be a model of chronic oxidative stress, excitotoxicity and neuronal damage. Reactive astrocytosis, chronic oxidative and excitotoxic stress, neuron loss and the susceptibility to seizure in the Dach-SMOX are discussed here. This genetic model would help researchers understand the linkage between polyamine dysregulation and neurodegeneration and unveil the roles of polyamines in the crosstalk between astrocytes and neurons in neuroprotection or neurodegeneration.

Keywords: mouse genetic model; neuron damage; polyamine; reactive astrocytosis; spermine oxidase.

Figure 1

Enzymes involved in PA biosynthesis (encircled) and catabolism (boxed). ODC, ornithine decarboxylase enzyme; PAOX, N1-acetylpolyamine oxidase; SAT1, spermidine/spermine N1-acetyltransferase; SMS, spermine synthase; SRM, spermidine synthase. The enzyme spermine oxidase (SMOX), which is overexpressed in the Dach-SMOX mice model, is highlighted in red.

Figure 2

Spermine oxidase chemical reaction. Spermine (Spm) is oxidized to produce spermidine (Spd), 3-aminopropanal (3-AP) and hydrogen peroxide (H₂O₂).

Figure 3

Schematic representation of the major mechanisms involved in neuronal damage resulting from polyamine dyshomeostasis in the central nervous system. Polyamine dyshomeostasis-dependent mechanisms that have been suggested to play pivotal roles in representative relevant diseases are also highlighted. AD, Alzheimer’s disease; DR, diabetic retinopathy; HIV D, HIV-associated dementia; PD, Parkinson’s disease.

Figure 4

SMOX overexpression in neurons resulted in chronic oxidative and excitotoxic stress and in neuron loss. Schematic representation of the main mechanisms taking place at cerebrocortical glutamatergic synapses in the SMOX-overexpressing mouse model. NeuN positive cells were reduced [37,121], and a relative increase in the abundance of astrocyte processes and a decrease in nerve terminals (an increase in GFAP, ezrin and vimentin-positive cells vs. a reduction in synaptophysin and NeuN-positive cells) were found. SMOX overexpression in neurons leads to oxidative stress in neurons, increased by an ROS response in astrocytes and leading to the depletion of catalase (a reduction in the antioxidant defence in nerve terminals). A defective control of the AMPA-evoked intracellular Ca²⁺ response in the nerve terminals can exacerbate the reactive astrocytes-dependent excitotoxic mechanism activation. For further details, see the text. AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor; Glu, glutamate; SMOX, spermine oxidase; Spm, spermine.