A53T-\u03b1-synuclein overexpression in murine locus coeruleus induces Parkinson\u2019s disease-like pathology in neurons and glia

Martin Timo Henrich,Lina Anita Matschke,Lars Timmermann,Jonathan Michael Brotchie,Niels Decher,Wei-Hua Chiu,James Benjamin Koprich,Fanni Fruzsina Geibl,Bolam Lee,Wolfgang Hermann Oertel

doi:10.1186/s40478-018-0541-1

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.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disorder [2] characterized by progressive degeneration of dopaminergic (DA) substantia nigra (SN) neurons and their striatal axon terminals [40, 68]
Since the prodromal phase is seen as the ideal time window for applying disease-modifying therapy [60, 92], it is of high importance to establish animal models, which allow testing of new and future therapeutic approaches on brain structures that are affected during prodromal PD
We show that targeted viral vector-mediated overexpression of human mutant A53T-article misfolded α-synuclein (aSYN) in vivo in locus coeruleus (LC) neurons of wild-type mice resulted in progressive LC neurodegeneration over a time frame of 9 weeks

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disorder [2] characterized by progressive degeneration of dopaminergic (DA) substantia nigra (SN) neurons and their striatal axon terminals [40, 68]. The degeneration of DA SN neurons and the onset of motor dysfunction are preceded by a latency of several years, if not decades, in which the PD pathology develops in brain regions outside the DA SN This phase, termed prodromal PD, is clinically characterized by the occurrence. Experimental evidence indicates that toxin-induced LC cell loss sensitized DA SN neurons for neurodegeneration [9, 22], whereas noradrenergic hyperinnervation resulted in neuroprotective effects [41] This data implies that LC neurodegeneration itself plays a double role by firstly being responsible for several non-motor symptoms and secondly for accelerating the progression of PD at the nigral level [27]. They exhibit an intrinsic pacemaking activity, generating action potentials continuously [55] thereby raising their basal metabolic stress level [78]

Objectives

Methods

Results

Discussion

Conclusion