Spermidine protects against α-synuclein neurotoxicity

Abstract

These authors contributed equally to this work.Keywords: autophagy, aging, a-synuclein, dopaminergic neuron loss, motor dysfunction, neurodegeneration, Parkinson's disease, SpermidineAs our society ages, neurodegenerative disorders like Parkinson`s disease (PD) are increasing in pandemic proportions. While mechanistic understanding of PD is advancing, a treatment with well tolerable drugs is still elusive. Here, we show that administration of the naturally occurring polyamine spermidine, which declines continuously during aging in various species, alleviates a series of PD-related degenerative processes in the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, two established model systems for PD pathology. In the fruit fly, simple feeding with spermidine inhibited loss of climbing activity and early organismal death upon heterologous expression of human a-synuclein, which is thought to be the principal toxic trigger of PD. In this line, administration of spermidine rescued a-synuclein-induced loss of dopaminergic neurons, a hallmark of PD, in nematodes. Alleviation of PD-related neurodegeneration by spermidine was accompanied by induction of autophagy, suggesting that this cytoprotective process may be responsible for the beneficial effects of spermidine administration.

Autophagic activity in neuronal cell death

“…Notably, a number of these therapies have been achieved with approved drugs, such as rapamycins [71,[111][112][113][114] , rilmenidine [110] . Furthermore, benefi ts have been seen in a number of animal models with the polyamine spermidine, which induces autophagy [115] .…”

“…Parkinson's disease Reductions in α-synuclein accumulation, alleviation of [113], [114] neurodegenerative behavior in mice Rilmenidine Huntington's disease Autophagy induction; enhanced clearance of mutant [110] Htt, improved motor performance in mice Spermidine Parkinson's disease Autophagy induction; Improved motor performance in [115] fruit fl y, reduced dopaminergic neuron loss in nematodes Arctigenin Alzheimer's disease Autophagy induction; Reduction in Aβ plaques through [117] inhibition of formation and enhanced clearance, improved memory in mice GTM-1 Alzheimer's disease Autophagy induction and increased fl ux; removal of Aβ [116] oligomers, cognitive improvements in mice Glucosylceramide inhibitors Niemann-Pick Type-C 1 Correction of autophagic fl ux; improved clearance of [119], [120] cholesterol and autophagic vesicles in mouse and cat models, prolonged neuron survival Genetic TFEB Alzheimer's disease Upregulation of lysosomal and autophagy genes; [124] Huntington's disease enhanced clearance of tau, α-synuclein, and mutant [25] Parkinson's disease Htt aggregates [67] …”

“…Notably, a number of these therapies have been achieved with approved drugs, such as rapamycins [71,[111][112][113][114] , rilmenidine [110] . Furthermore, benefi ts have been seen in a number of animal models with the polyamine spermidine, which induces autophagy [115] .A variety of strategies aimed at a number of targets have adopted this concept, with some encouraging fi ndings. Agents like the small molecule GTM-1 and natural product arctigenin both enhance autophagic clearance, and are associated with reductions in toxic aggregates and improved cognition in AD mouse models [116,117] .…”

Parkinson’s Disease: Insights from Drosophila Model

“…mTor-independent pathways/unknown Spermidine α-synuclein Reduced motor dysfunction, increased lifespan; Reduced neuronal cell loss [194] LRKK2 kinase inhibitors GW5074, and sorafenib α-synuclein Protect again DA neuron degeneration locomotor activity [183] Histone Deacetylase inhibitors α-synuclein Protect again DA locomotor activity [195] Antitumor agents Geldanamycin α-synuclein Protect again DA Mobilized the stress response and increase levels of chaperon HSP70 [195] * All treatments were administered as dietary complement. …”

Autophagy in neurodegenerative diseases: From pathogenic dysfunction to therapeutic modulation

“…This molecule activates autophagy and prolongs lifespan through the inhibition of EP300, an acetyltransferase that represses autophagy genes by histone acetylation [172].…”