Astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson’s disease: removing axonal debris

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.

ALS2-related disorders in Spanish children

ALS2 gene encoding for alsin protein is responsible for neurological disorders due to retrograde degeneration of the upper motor neurons of the pyramidal tracts, inherited in an autosomal recessive manner, and displaying a clinical continuum including the infantile ascending hereditary spastic paraplegiaidentified in three Spanish children presented here.

Direct and transsynaptic retrograde degeneration and optic nerve head microvascular changes in patients with hemianopia

Purpose: To investigate optic nerve head (ONH) microvascular changes secondary to transsynaptic retrograde degeneration (TRD), comperatively with direct retrograde degeneration and healthy controls. Methods: Patients with hemianopia due to intracranial lesion included in the study. Intracranial lesion was categorized by location: postgeniculate (causing TRD), chiasmal (causing direct retrograde degeneration). For the postgeniculate lesions, the eye on the same side of the lesion was defined as the ipsilateral eye and the eye on the opposite side as the contralateral eye. Optic disc microvasculature was evaluated with the help of optic coherence tomography angiography. Results: Sixteen eyes of 16 patients with chiasmal lesion, 28 eyes of 14 patients with postgeniculate lesion, and 30 eyes of 30 healthy subjects were included in the study. Ipsilateral eyes of the patients with postgeniculate lesion had decreased vessel density at the temporal sectors compatible with the affected nasal side of the visual field. Contralateral eyes showed no reduction of the vessel density at the affected nasal sectors. The eyes with chiasmal lesions had decreased vessel density at the peripapillary region and nasal half of the ONH compatible with temporal hemianopia. Vascular changes in the chiasmal lesion were more prominent than those of the postgeniculate lesion. Retinal nerve fiber layer and ganglion cell complex thickness were reduced. Conclusion: Vessel density of ONH was reduced in patients with homonymous hemianopia, providing evidence for TRD secondary to acquired postgeniculate lesion. Direct retrograde degeneration was more prominent in affected sectors when compared to TRD.

Correction to: Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis

In the original publication of this article [1], Fig. 10 contained two panels “C” as panel “F” was accidentally omitted. The incorrect (Fig. 1) and correct (Fig. 2) versions are published in this correction article.

Long distance retrograde degeneration of the retino-geniculo-cortical pathway in homonymous hemianopia

Long-distance retrograde degeneration of the retino-geniculo-cortical pathway has been described in humans and animal models following injury to the brain. In this study, we used optical coherence tomography (OCT) to measure the severity and timing of retrograde degeneration after post-chiasmal visual pathway lesions in patients with homonymous hemianopia. We performed a retrospective study of 69 patients with homonymous hemianopia and analyzed high quality OCT macular ganglion cell complex (GCC) and retinal nerve fiber layer (RNFL). Patients with lesions involving the optic tract and thalamus were included in the anterior group, while patients with lesions of the occipital lobe were included in the posterior group. Statistical significance was determined using Mann-Whitney U test and Wilcoxon test. We found that in patients with homonymous hemianopia, those with anterior lesion exhibited earlier and more severe thinning compared with the posterior group. In fact, thinning can occur within 2 months after insult in the anterior group. Within 6 months of onset, the anterior group exhibited about 5 times more hemi-macular GCC thinning than those with acquired lesions of the posterior visual pathway (P = 0.0023). Although the severity of hemi-macular GCC thinning was different, the majority of hemi-macular thinning occurred within the first 6 months in both groups. Beyond 2 years, thinning in those with acquired anterior and posterior lesions was minimal, except in a small number of patients with multiple insults to the occipital lobe. In conclusion, using OCT, we measured the severity and rate of long-distance, retrograde degeneration in patients with homonymous hemianopia. Homonymous hemi-macular thinning after optic tract and thalamic injury was more severe and occurred earlier compared with thinning after occipital lobe insult via trans-synaptic degeneration. The presence of severe hemi-macular degeneration on OCT provides objective evidence that localizes the lesion to the post-chiasmal anterior visual pathway.