Monoamine oxidase and α-synuclein as targets in Parkinson’s disease therapy

Abstract

The degeneration of dopaminergic neurons in Parkinson’s disease (PD) is suggested to be associated with the generation of cytotoxic products from dopamine (DA) metabolism and the formation of fibrillar inclusions of the protein α-synuclein (AS). Despite of the role of AS in the pathogenesis of PD is not completely understood, the stabilization of nontoxic aggregates could represent a potential therapeutic route. In respect to the DA metabolism, a well-established strategy is the inhibition of the enzyme monoamine oxidase, which is responsible to catalyze the major route of inactivation of neurotransmitters. Although pharmacological strategies to treat different aspects of the parkinsonian condition are under investigation, the development of multifunctional molecules that act simultaneously on different targets associated to PD has gained attention only recently. In this work we examine the biochemical properties of synthetic and natural molecules that are capable of interfering on both DA system (via monoamine oxidase inhibition) and AS fibrillation.

Keywords::

• α-synuclein
• dopamine
• fibrils
• monoamine oxidase
• oxidative stress
• Parkinson’s disease
• protofibrils

Financial & competing interests disclosure

C Follmer has received grants from the International Foundation for Science (IFS), Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The high selectivity of neuronal degeneration in Parkinson’s disease (PD) reinforces the hypothesis that catecholamine neurons produce specific neurotoxins whose accumulation might trigger neuronal death.

• The idea that monoamine oxidase (MAO) plays a central role in neuropathogenesis of PD was reinforced by data that demonstrated that the aldehydes generated from catecholamine oxidation by MAO action might promote oxidative stress and neuron death.

• The stabilization of non-toxic aggregates of α-synuclein (AS) might represent an important strategy in the development of new therapies for PD.

• The aggregation and neurotoxicity of AS seem to correlate precisely, suggesting that the role of in PD AS is likely associated with its aggregation rather than loss of physiological function.

• The interaction of AS with either oxidized derivatives of dopamine (e.g., dopaminochrome) or 3,4-dihydroxyphenylacetaldehyde could lead to an increase in the levels of potentially toxic protein aggregates.

• In addition to MAO inhibitory activity, certain bioactive polyphenols (flavonoids and non-flavonoids) exhibit anti-fibrillogenic activity on AS, which might be in part associated with the ability of these compounds to be spontaneously oxidized to hydroquinones and quinones.

• Selegiline might behave as multifunctional drug for PD by inhibiting both MAO activity and the formation of toxic aggregates of AS.

• Regarding the wide-spectrum biochemical properties of curcumin and the fact this molecule can cross the blood–brain barrier, curcumin might considered a potential multifunctional neuroprotective agent for PD and possibly for other neurodegenerative disorders.

Notes