A53T-α-synuclein overexpression in murine locus coeruleus induces Parkinson’s disease-like pathology in neurons and glia

Abstract

Degeneration of noradrenergic locus coeruleus neurons occurs during the prodromal phase of Parkinson’s disease and contributes to a variety of non-motor symptoms, e.g. depression, anxiety and REM sleep behavior disorder. This study was designed to establish the first locus coeruleus α-synucleinopathy mouse model, which should provide sufficient information about the time-course of noradrenergic neurodegeneration, replicate cardinal histopathological features of the human Parkinson’s disease neuropathology and finally lead to robust histological markers, which are sufficient to assess the pathological changes in a quantitative and qualitative way. We show that targeted viral vector-mediated overexpression of human mutant A53T-α-synuclein in vivo in locus coeruleus neurons of wild-type mice resulted in progressive noradrenergic neurodegeneration over a time frame of 9 weeks. Observed neuronal cell loss was accompanied by progressive α-synuclein phosphorylation, formation of proteinase K-resistant α-synuclein-aggregates, accumulation of Ubi-1- and p62-positive inclusions in microglia and induction of progressive micro- and astrogliosis. Apart from this local pathology, abundant α-synuclein-positive axons were found in locus coeruleus output regions, indicating rapid anterograde axonal transport of A53T-α-synuclein. Taken together, we present the first model of α-synucleinopathy in the murine locus coeruleus, replicating essential morphological features of human Parkinson’s disease pathology. This new model may contribute to the research on prodromal Parkinson’s disease, in respect to pathophysiology and the development of disease-modifying therapy.

The locus coeruleus: Another vulnerability target in Parkinson's disease

“…The studies conducted so far on LC vulnerability and degeneration in PD animal models (Table ) further reveal that neurotoxins which are commonly used to lesion the nigrostriatal system (e.g., MPTP or the pesticide rotenone) also cause degeneration of the LC. Furthermore, aSYN‐overexpression models demonstrate that LC cells are susceptible to artificially increased intracellular aSYN levels . Compared to the wealth of studies conducted on the SNc, research on the LC in the preclinical as well as in the clinical setting is sparse.…”

“…Furthermore, aSYN-overexpression models demonstrate that LC cells are susceptible to artificially increased intracellular aSYN levels. 23 Compared to the wealth of studies conducted on the SNc, 24 research on the LC in the preclinical as well as in the clinical setting is sparse. This situation offers the unique opportunity to transfer the existing expertise on catecholaminergic neurons and the fast growing body of knowledge on the nigrostriatal system to research on the LC-noradrenergic system.…”

The connectome is necessary but not sufficient for the spread of alpha-synuclein pathology in rats

“…Such artefacts may overestimate the size of the source focus sending projections to other brain areas. Therefore, additional connectivity data with more highly resolved structure-specific projection data for certain key brain structures, e.g., DMX or LC (Henrich et al 2018), might allow a more refined prediction of the contribution of the connectome to the spread of pathology. Nevertheless, we do not believe such data would affect our overall conclusion that the connectome is necessary but not sufficient to explain the patterns of spreading of alpha -synuclein pathology in rats.…”

JN403, an alpha-7-nicotine-acetylcholine-receptor agonist, reduces alpha-synuclein induced inflammatory parameters ofin vitromicroglia but fails to attenuate the reduction of TH positive nigral neurons in a focal alpha-synuclein overexpression mouse model of Parkinson’s disease

“…It has been studied as a common model to study the α Syn toxicity in the SNc including ours [28], in this study, we proposed a neuroprotective effect of a phosphodiesterase 1 inhibitor using a viral vector-mediated wild-type α Syn overexpression. Moreover, other PD-vulnerable neuronal populations such as the locus coeruleus [29] and the dorsal motor nucleus of the vagal nerve [30] have been investigated using the viral-mediated overexpression model.…”