RT info:eu-repo/semantics/article
T1 Astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson¿s disease: removing axonal debris.
A1 Morales Pérez, Ingrid
A1 Puertas Avendaño, Ricardo
A1 Sánchez, Alberto
A1 Pérez Barreto, Adrián
A1 Rodríguez Sabaté, Clara
A1 Rodríguez, Manuel
A2 Ciencias Médicas Básicas
A2 Grupo de Neurobiología y Neurología Experimental
K1 Astrocyte
K1 Phagocytosis
K1 Parkinson’s disease
K1 Dying‑back degeneration
K1 Medial forebrain bundle
K1 Spheroid
AB Objective: The dopaminergic nigrostriatal neurons (DA cells) in healthy people present a slow degeneration with aging, which produces cellular debris throughout life. About 2%–5% of people present rapid cell degeneration of more than 50% of DA cells, which produces Parkinson’s disease (PD). Neuroinflammation accelerates the cell degeneration and may be critical for the transition between the slow physiological and the rapid pathological degeneration of DA cells, particularly when it activates microglial cells of the medial forebrain bundle near dopaminergic axons. As synaptic debris produced by DA cell degeneration may trigger the parkinsonian neuroinflammation, this study investigated the removal of axonal debris produced by retrograde degeneration of DA cells, paying particular attention to the relative roles of astrocytes and microglia. Methods: Rats and mice were injected in the lateral ventricles with 6‑hydroxydopamine, inducing a degeneration of dopaminergic synapses in the striatum which was not accompanied by non‑selective tissue damage, microgliosis or neuroinflammation. The possible retrograde degeneration of dopaminergic axons, and the production and metabolization of DA‑cell debris were studied with immunohistochemical methods and analyzed in confocal and electron microscopy images. Results: The selective degeneration of dopaminergic synapses in the striatum was followed by a retrograde degeneration of dopaminergic axons whose debris was found within spheroids of the medial forebrain bundle. These spheroids retained mitochondria and most (e.g., tyrosine hydroxylase, the dopamine transporter protein, and amyloid precursor protein) but not all (e.g., α‑synuclein) proteins of the degenerating dopaminergic axons. Spheroids showed initial (autophagosomes) but not late (lysosomes) components of autophagy (incomplete autophagy). These spheroids were penetrated by astrocytic processes of the medial forebrain bundle, which provided the lysosomes needed to continue the degradation of dopaminergic debris. Finally, dopaminergic proteins were observed in the cell somata of astrocytes. No microgliosis or microglial phagocytosis of debris was observed in the medial forebrain bundle during the retrograde degeneration of dopaminergic axons. Conclusions: The present data suggest a physiological role of astrocytic phagocytosis of axonal debris for the medial forebrain bundle astrocytes, which may prevent the activation of microglia and the spread of retrograde axonal degeneration in PD.
YR 2021
FD 2021
LK http://riull.ull.es/xmlui/handle/915/38588
UL http://riull.ull.es/xmlui/handle/915/38588
LA en
DS Repositorio institucional de la Universidad de La Laguna
RD 25-nov-2024