Objective: The objective of this work is to develop a unique mouse model of spreading α-synucleinopathy to accelerate the development of novel disease-modifying treatments for Parkinson’s disease (PD) and other synucleinopathies.

Background: In PD, non-motor deficits, such as olfactory impairment and sleep disturbances, typically precede the cardinal motor symptoms by several years. In this study, we characterized functional, structural, and pathologic changes associated with the olfactory system in an inducible mouse model of α-synucleinopathy using behavioral testing, in vivo magnetic resonance imaging (MRI), and quantitative immunohistochemistry (qIHC).

Methods: The mouse model of α-synucleinopathy was induced in M83 transgenic (Tg) mice by stereotaxic inoculation of human preformed α‐synuclein fibrils (PFFs) into the anterior olfactory nucleus (AON). Animals were tested for olfactory deficits using the buried pellet test and for sleep dysfunctions using the PiezoSleep Mouse Behavior Tracking System. Anatomical MRI scans were acquired at baseline and follow-up (at 2, 3, and 4 months post-inoculation of PFFs), and images were processed using Biospective’s fully-automated NIGHTWING™ software. Anatomical regional volumes and cortical thickness measures were assessed. Finally, qIHC studies were performed to assess α-synucleinopathy, neurodegeneration, and neuroinflammation using Biospective’s PERMITS™ software.

Results: Injection of PFFs into the AON induced statistically significant olfactory deficits, as measured by the latency in the buried pellet test in Tg mice compared to control animals. Injection of PFFs into the AON also had an impact on the quality of sleep of Tg mice compared to control animals. The α-synuclein pathology was observed in anatomically-connected olfactory regions in Tg mice. Quantitative analysis of the MRI data revealed that injection of PFFs into the AON resulted in significant decreases in regional neuroanatomical volumes associated with loss of neurons in those regions in Tg mice.

Conclusions: We have developed a unique mouse model of spreading α-synucleinopathy that demonstrates olfactory dysfunction and structural brain changes. This model is well-suited for preclinical efficacy studies to accelerate the development of novel disease-modifying treatments for PD and other synucleinopathies.

« Back to 2018 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/olfactory-dysfunction-sleep-disturbances-neuronal-loss-and-regional-brain-atrophy-in-an-inducible-mouse-model-of-alpha-synucleinopathy/