Cholinergic neurons within the nucleus basalis magnocellularis in bilaterally lesioned rats with 192IgG-saporin.

En el presente estudio se han estudiado las neuronas colinérgicas del núcleo basal magnocelular y sus áreas de proyección en ratas lesionadas bilateralmente con la inmunotoxina 192IgG-saporina

Striatal synaptic bioenergetic and autophagic decline in premotor experimental parkinsonism

Synaptic impairment might precede neuronal degeneration in Parkinson’s disease. However, the intimate mechanisms altering synaptic function by the accumulation of presynaptic α-synuclein in striatal dopaminergic terminals before dopaminergic death occurs, have not been elucidated. Our aim is to unravel the sequence of synaptic functional and structural changes preceding symptomatic dopaminergic cell death. As such, we evaluated the temporal sequence of functional and structural changes at striatal synapses before parkinsonian motor features appear in a rat model of progressive dopaminergic death induced by overexpression of the human mutated A53T α-synuclein in the substantia nigra pars compacta, a protein transported to these synapses. Sequential window acquisition of all theoretical mass spectra proteomics identified deregulated proteins involved first in energy metabolism and later, in vesicle cycling and autophagy. After protein deregulation and when α-synuclein accumulated at striatal synapses, alterations to mitochondrial bioenergetics were observed using a Seahorse XF96 analyser. Sustained dysfunctional mitochondrial bioenergetics was followed by a decrease in the number of dopaminergic terminals, morphological and ultrastructural alterations, and an abnormal accumulation of autophagic/endocytic vesicles inside the remaining dopaminergic fibres was evident by electron microscopy. The total mitochondrial population remained unchanged whereas the number of ultrastructurally damaged mitochondria increases as the pathological process evolved. We also observed ultrastructural signs of plasticity within glutamatergic synapses before the expression of motor abnormalities, such as a reduction in axospinous synapses and an increase in perforated postsynaptic densities. Overall, we found that a synaptic energetic failure and accumulation of dysfunctional organelles occur sequentially at the dopaminergic terminals as the earliest events preceding structural changes and cell death. We also identify key proteins involved in these earliest functional abnormalities that may be modulated and serve as therapeutic targets to counterbalance the degeneration of dopaminergic cells to delay or prevent the development of Parkinson’s disease.This study was funded by the Instituto de Salud Carlos III through the projects PI14/00763 and PI19/01915 (co-funded by ERDF/ESF, ‘Investing in your future’). L.M.-G. held a Predoctoral Research Fellowship from the University of the Basque Country (UPV/EHU). T.R.-C. and A.Q.-V. were funded by CIBERNED. T.R.-C. held a Fundación Jesús de Gangoiti Barrera Foundation grant (Bilbao, Spain). H.J.-U. and A.B.-I. held a Predoctoral Research Fellowship from the Government of the Basque Country. Israel Science Foundation (536/19) and the Spanish Ministry of Science (SAF2016-78071-R) funded the contribution of S.K. and A.O

Synaptic dysfunction in Parkinson's Disease: functional and ultrastructural study of the striatal synapses in an animal model of progressive parkinsonism

212 p.This Ph.D. project involves the temporal sequence of the earliest functional and structural events in the striatal synapses in a rat model of progressive parkinsonism induced by overexpression of human ¿-synuclein (h¿-syn) with A53T mutation (rAAV-h¿-syn) in the substantia nigra compacta (SNc), before parkinsoniasn motor features appear. We have observed a sequential pattern of events. The aggregation of h¿-syn in the striatal dopaminergic terminals firstly induces deregulation of proteins affecting metabolism followed by decreased mitochondrial respiration in striatal synaptosomes. Differential analysis by proteomics revealed significant deregulated proteins from biological pathways related to synaptic function and neurotransmission. These functional and proteostatic alterations precede the structural changes and the onset of degeneration of the dopaminergic axons in the striatum that precede the loss of neuronal soma in the SNc. Lastly, homeostatic changes in glutamatergic synapses are simultaneous to the onset of the synaptic functional deficit, and dendritic spine loss is accompanied by plastic events. These last findings could represent compensatory mechanisms to maintain normal function during the onset of dopaminergic degeneration. We count with a good model of progressive synaptopathy in the dopaminergic pathway linked to the accumulation of h¿-syn, providing an excellent preclinical model to develop new synapse-targeted therapies

Correction to: Motor impulsivity and delay intolerance are elicited in a dose-dependent manner with a dopaminergic agonist in parkinsonian rats.

In the original version of this article, the Figure 3 was published in an incorrect format, even though the data and the related information in the text are correct

Pramipexole-induced impulsivity in mildparkinsonian rats: a model of impulse control disorders in Parkinson's disease

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