Synaptic Regulator α-Synuclein in Dopaminergic Fibers Is Essentially Required for the Maintenance of Subependymal Neural Stem Cells

Perez-Villalba A(1)(2)(3), Sirerol-Piquer MS(1)(2)(3), Belenguer G(1)(2)(3), Soriano-Cantón R(1)(2)(3), Muñoz-Manchado AB(1)(4)(5), Villadiego J(1)(4)(5), Alarcón-Arís D(6)(7)(8), Soria FN(9)(10), Dehay B(9)(10), Bezard E(9)(10), Vila M(1)(11)(12), Bortolozzi A(6)(7)(8), Toledo-Aral JJ(1)(4)(5), Pérez-Sánchez F(13)(2)(3), Fariñas I(13)(2)(3).

Author information:
(1)Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, ISCIII, 28029 Madrid, Spain.
(2)Departamento de Biología Celular, Biología Funcional y Antropología Física and.
(3)Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina, Universidad de Valencia, 46100 Burjassot, Spain.
(4)Departamento de Fisiología Médica y Biofísica and.
(5)Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain.
(6)Department of Neurochemistry and Neuropharmacology, IIBB-CSIC and.
(7)Institut d’Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona,  Spain.
(8)Centro de Investigación Biomédica en Red de Salud Mental, ISCIII, 28029 Madrid, Spain.
(9)Université de Bordeaux, Institut des Maladies Neurodégénératives, Unité Mixte de Recherche 5293 and.
(10)Centre National de la Recherche Scientifique, Institut des Maladies Neurodégénératives, Unité Mixte de Recherche 5293, 33076 Bordeaux, France.
(11)Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute, Autonomous University of Barcelona, 08035, Barcelona, Spain, and.
(12)Catalan Institution for Research and Advanced Studies, 08010 Barcelona, Spain.
(13)Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas,
ISCIII, 28029 Madrid, Spain,

Synaptic protein α-synuclein (α-SYN) modulates neurotransmission in a complex and poorly understood manner and aggregates in the cytoplasm of degenerating neurons in Parkinson’s disease. Here, we report that α-SYN present in dopaminergic nigral afferents is essential for the normal cycling and maintenance of neural stem cells (NSCs) in the brain subependymal zone of adult male and female mice. We also show that premature senescence of adult NSCs into non-neurogenic astrocytes
in mice lacking α-SYN resembles the effects of dopaminergic fiber degeneration resulting from chronic exposure to 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine or intranigral inoculation of aggregated toxic α-SYN. Interestingly, NSC loss in α-SYN-deficient mice can be prevented by viral delivery of human α-SYN into their sustantia nigra or by treatment with l-DOPA, suggesting that α-SYN regulates dopamine availability to NSCs. Our data indicate that α-SYN, present in dopaminergic nerve terminals supplying the subependymal zone, acts as a niche component to sustain the neurogenic potential of adult NSCs and identify α-SYN and DA as potential targets to ameliorate neurogenic defects in the aging and
diseased brain.SIGNIFICANCE STATEMENT We report an essential role for the protein α-synuclein present in dopaminergic nigral afferents in the regulation of adult neural stem cell maintenance, identifying the first synaptic regulator with an implication in stem cell niche biology. Although the exact role of  α-synuclein in neural transmission is not completely clear, our results indicate that it is red for stemness and the preservation of neurogenic potential in concert with dopamine.

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