Lysines, Achilles’ heel in alpha-synuclein conversion to a deadly neuronal endotoxin

• Alpha-synuclein aggregation is a key mechanism in neurodegenerative disorders.
• Several aldehydes are accumulated in parkinsonian or ageing brains.
• Alpha-synuclein lysines are targets for chemical modification by aldehydes.
• Aldehydes and alpha-synuclein may act synergically leading to neurodegeneration

Alpha-synuclein aggregation is associated with Parkinson’s disease and other neurodegenerative disorders termed synucleinopathies. The sequence of alpha-synuclein has a remarkable amount of lysines, which may be a target for modifications by several aldehydes found at increased concentration in parkinsonian brains. The involved aldehydes are the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde, the lipid peroxidation products 4-hydroxynonenal, acrolein and malondialdehyde, and advanced glycation end-products. Moreover, both relative expression levels and enzymatic activity of aldehyde dehydrogenases, which are responsible for aldehydes detoxification in cells, are altered in Parkinson's disease brains. The effects of aldehyde modifications can include: (i) a perturbation in the equilibrium of cytosolic and membrane-bound alpha-synuclein, that may alter protein function and lead to aggregation; (ii) the reduction of alpha-synuclein ubiquitination and SUMOylation, affecting its cellular localization and clearance; (iii) a decreased susceptibility to cleavage at specific sites by extracellular proteases; (iv) a reduced availability of identified lysine acetylation sites; (v) the production of toxic oligomeric alpha-synuclein-aldehyde species, able to damage lipid membranes and transmissible from unhealthy to healthy neurons. All of these observations point to a complex interaction between alpha-synuclein and aldehydes in brain, which may lead to the accumulation of dysfunctional alpha-synuclein and its oligomerization.