Alterations in the nigrostriatal system following conditional inactivation of α-synuclein in neurons of adult and aging mice

NEUROBIOLOGY OF AGING

卷:91

Article

Ninkina, Natalia^1,2  Tarasova, Tatiana, V^1,2  Chaprov, Kirill D.^1,2  Roman, Andrei Yu^1,2  Kukharsky, Michail S.^2,3,4  Kolik, Larisa G.³  Oychinnikov, Ruslan^2,4  Ustyugov, Aleksey A.^1,2  Durnev, Andrey D.³  Buchman, Vladimir L.^1,2 

[1] Cardiff Univ, Sch Biosci, Museum Ave, Cardiff CF10 3AX, Wales

[2] Inst Physiol Act Cpds Russian Acad Sci IPAC RAS, Moscow, Moscow Region, Russia

[3] FSBI Res Zakusov Inst Pharmacol FSBI RZIP, Moscow, Russia

[4] Pirogov Russian Natl Res Med Univ, Moscow, Russia

关键词: Dopaminergic neurons;    Substantia nigra;    Conditional knockout;    Dopamine turnover;    Parkinson's disease;   

DOI  :  10.1016/j.neurobiolaging.2020.02.026

来源: Elsevier

【 摘 要 】

The etiology and pathogenesis of Parkinson's disease (PD) are tightly linked to the gain-of-function of alpha-synuclein. However, gradual accumulation of alpha-synuclein aggregates in dopaminergic neurons of substantia nigra pars compacta (SNpc) leads to the depletion of the functional pool of soluble alpha-synuclein, and therefore, creates loss-of-function conditions, particularly in presynaptic terminals of these neurons. Studies of how this late-onset depletion of a protein involved in many important steps of neurotrans-mission contributes to PD progression and particularly, to worsening the nigrostriatal pathology at late stages of the disease are limited and obtained data, are controversial. Recently, we produced a mouse line for conditional knockout of the gene encoding alpha-synuclein, and here we used its tamoxifen-inducible panneuronal inactivation to study consequences of the adult-onset (from the age of 6 months) and late-onset (from the age of 12 months) alpha-synuclein depletion to the nigrostriatal system. No significant changes of animal balance/coordination, the number of dopaminergic neurons in the SNpc and the content of dopamine and its metabolites in the striatum were observed after adult-onset alpha-synuclein depletion, but in aging (18-month-old) late-onset depleted mice we found a significant reduction of major dopamine metabolites without changes to the content of dopamine itself. Our data suggest that this might be caused, at least partially, by reduced expression of aldehyde dehydrogenase ALDH1a1 and could lead to the accumulation of toxic intermediates of dopamine catabolism. By extrapolating our findings to a potential clinical situation, we suggest that therapeutic downregulation of alpha-synuclein expression in PD patients is a generally safe option as it should not cause adverse side effects on the functionality of their nigrostriatal system. However, if started in aged patients, this type of therapy might trigger slight functional changes of the nigrostriatal system with potentially unwanted additive effect to already existing pathology. (C) 2020 The Author(s). Published by Elsevier Inc.

【 授权许可】

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