Selective α-synuclein overexpression-induced pathology in noradrenergic neurons: a new mouse model for prodromal Parkinson’s disease?

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Abstract

Objective: To investigate the phenotype of noradrenergic (NA) neurons in an animal model with selective overexpression of α-synuclein (αSyn) in the locus coeruleus (LC) with histological, physiological and behavioral methods.

Background: Transgenic rodents, viral vector-based focal overexpression of αSyn or inoculation with preformed fibrils of αSyn have been used for modeling Parkinson’s disease (PD). These experimental approaches have limitations: 1) they lack specificity for subclasses of neurons which are differentially affected during the various stages of PD; 2) tend to focus mainly on degeneration of the dopaminergic substantia nigra compacta (SNc). In contrast, few data are available on the LC in PD animal models, which is early affect in PD by αSyn-pathology and the main source of NA projections in the brain.

Materials and Methods: To allow selective overexpression of αSyn in the LC neurons we designed a tyrosine hydroxylase (TH) promoter controlled recombinant adeno-associated virus (AAV) 2/5 vector carrying human-wildtype αSyn. This vector was injected into the right LC of the mouse brain. Histological analysis and whole-cell patch-clamp recording were performed at 9 weeks of αSyn overexpression followed by ongoing long-term evaluation at 24 weeks. The degree of the αSyn burden in selective regions of interest was quantified. Motor and non-motor related behavioral assays were also employed at 9 and 24 weeks.

Results: We report over 98% of the αSyn transduction rate specifically in the LC neurons. Mild loss of TH+ neurons in the LC was found. In addition, markers of αSyn-aggregation (αSyn phosphorylated at Serine 129, Ubi1 and p62) and of gliosis were observed in the LC. Interestingly, the LC neurons revealed regular pacemaking activity of frequency and after-hyperpolarization amplitude at 9 weeks of αSyn overexpression. The whole-brain analysis showed αSyn propagation to distinctive LC-output regions, including limbic structures and the cortex. Motor test results demonstrated no significant alteration in locomotion and gait behaviors in αSyn groups. The results of the the non-motor related tasks will next be analyzed.

Conclusion: We will present histological, electrophysiological and behavioral data at 9 and 24 weeks in new mouse model with selective αSyn overexpression in LC neurons. We will discuss the advantages and limitations of this αSyn LC model for prodromal and early stage PD

Original languageEnglish
Article number813
JournalMovement disorders
Publication statusPublished - 20 Feb 2020

Keywords

  • Parkinson's disease; alpha-synuclein; autophagy-lysosomal pathway; glucocerebrosidase
  • parkinson's disease pathophysiology

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