Genetic inactivation of alpha-synuclein affects embryonic development of dopaminergic neurons of the substantia nigra, but not the ventral tegmental area, in mouse brain.

Tatiana V Tarasova,Alexandr I Antohin,Michail S Kukharsky,Valeria V Goloborshcheva,Larisa N Skuratovskaya,Ruslan K Ovchinnikov,Olga A Lytkina

doi:10.7717/peerj.4779

Abstract

Lesion of the dopaminergic neurons of the nigrostriatal system is a key feature of Parkinson’s disease (PD). Alpha-synuclein is a protein that is a major component of Lewy bodies, histopathological hallmarks of PD, and is involved in regulation of dopamine (DA) neurotransmission. Previous studies of knockout mice have shown that inactivation of alpha-synuclein gene can lead to the reduction in number of DA neurons in the substantia nigra (SN). DA neurons of the SN are known to be the most affected in PD patients whereas DA neurons of neighboring ventral tegmental area (VTA) are much less susceptible to degeneration. Here we have studied the dynamics of changes in TH-positive cell numbers in the SN and VTA during a critical period of their embryonic development in alpha-synuclein knockout mice. This precise study of DA neurons during development of the SN revealed that not only is the number of DA neurons reduced by the end of the period of ontogenic selection, but that the way these neurons are formed is altered in alpha-synuclein knockout mice. At the same time, DA neurons in the VTA are not affected. Alpha-synuclein exerts a modulating effect on the formation of DA neurons in the SN and has no effect on the formation of DA neurons in VTA, the structure that is much less susceptible to degeneration in a brain with PD, suggesting a potential role of alpha-synuclein in the development of the population of DA neurons in substantia nigra.

Highlights

Alpha-synuclein, a small natively unfolded protein abundantly expressed in vertebrate neurons, is involved in pathogenesis of certain neurodegenerative diseases
We analysed the sub-population of developing dopaminergic neurons within the substantia nigra in alpha-synuclein knockout mice and control wild type (WT) littermates on embryonic days E10.5, E11.5, E12.5 and E13.5
A small number of tyrosine hydroxylase (TH)-positive cells in the lateral region of the mesencephalon that represent the primordium of the substantia nigra (SN) were already detected by embryonic day E10.5 and no difference between knock-out and WT mice were revealed (Fig.1A)

Summary

Introduction

Alpha-synuclein, a small natively unfolded protein abundantly expressed in vertebrate neurons, is involved in pathogenesis of certain neurodegenerative diseases. Principal members of this group of diseases known as alphasynucleinopathies include, Parkinson’s disease, Lewy body dementia and multisystem atrophy, but alpha-synuclein pathology is often observed in the nervous system of patients with other neurodegenerative diseases (Goedert et al 2017). It is believed that the period between mouse embryonic days 11.5 and 13.5 when post-mitotic precursors of DA neurons are migrating from the ventricular zone located on the border between midbrain and forebrain to their sites in the SN and VTA where their final differentiation takes place, is a critical period in the process of forming these two neuronal populations This coincides with a dramatic increase of alpha-synuclein expression in midbrain nuclei (Abeliovich & Hammond 2007). Depletion of alpha-synuclein from developing neurons, leads to a smaller number of mature

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