Development of neuroprotective therapeutics for Parkinson’s disease (PD) is facing a lack of translation from pre-clinical to clinical trials. One strategy for improvement is to increase predictive validity of pre-clinical studies by using extensively characterized animal models with a comprehensive set of validated pharmacodynamic readouts. Mice over-expressing full-length, human, wild-type alpha-synuclein under the Thy-1 promoter (Thy1-aSyn line 61) reproduce key features of sporadic PD, such as progressive loss of striatal dopamine, alpha-synuclein pathology, deficits in motor and non-motor functions, and elevation of inflammatory markers. Extensive work with this model by multiple laboratories over the past decade further increased confidence in its robustness and validity, especially for analyzing pathomechanisms of alpha-synuclein pathology and down-stream pathways, and for pre-clinical drug testing. Interestingly, while postnatal transgene expression is widespread in central and peripheral neurons, the extent and progression of down-stream pathology differs between brain regions, thereby replicating the characteristic selective vulnerability of neurodegenerative diseases. In-depth characterization of these readouts in conjunction with behavioral deficits has led to more informative endpoints for pre-clinical trials. Each drug tested in Thy1-aSyn line 61 enhances knowledge on how molecular targets, pathology, and functional behavioral readouts are interconnected, thereby further optimizing the platform towards predictive validity for clinical trials. Here, we present the current state of the art using Thy1-aSyn line 61 for drug target discovery, validation, and pre-clinical testing.

Synucleinopathies are neurodegenerative disorders characterized by alpha-synuclein (αSyn) accumulation in neurons or glial cells, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). αSyn-related pathology plays a critical role in the pathogenesis of synucleinopathies leading to the progressive loss of neuronal populations in specific brain regions and the development of motor and non-motor symptoms. Anxiety is among the most frequent non-motor symptoms in patients with PD, but it remains underrecognized and undertreated, which significantly reduces the quality of life for patients. Anxiety is defined as a neuropsychiatric complication with characteristics such as nervousness, loss of concentration, and sweating due to the anticipation of impending danger. In patients with PD, neuropathology in the amygdala, a central region in the anxiety and fear circuitry, may contribute to the high prevalence of anxiety. Studies in animal models reported αSyn pathology in the amygdala together with alteration of anxiety or fear learning response. Therefore, understanding the progression, extent, and specifics of pathology in the anxiety and fear circuitry in synucleinopathies will suggest novel approaches to the diagnosis and treatment of neuropsychiatric symptoms. Here, we provide an overview of studies that address neuropsychiatric symptoms in synucleinopathies. We offer insights into anxiety and fear circuitry in animal models and the current implications for therapeutic intervention. In summary, it is apparent that anxiety is not a bystander symptom in these disorders but reflects early pathogenic mechanisms in the cortico-limbic system which may even contribute as a driver to disease progression.

A BS TRACT: Background: Venglustat is a brain-penetrant, small molecule inhibitor of glucosylceramide synthase used in clinical testing for treatment of Parkinson's disease (PD). Despite beneficial effects in certain cellular and rodent models, patients with PD with mutations in GBA, the gene for lysosomal glucocerebrosidase, experienced worsening of their motor function under venglustat treatment (NCT02906020, MOVES-PD, phase 2 trial). Objective: The objective of this study was to evaluate venglustat in mouse models of PD with overexpression of wild-type α-synuclein. Methods: Mice overexpressing α-synuclein (Thy1-aSyn line 61) or Gba-mutated mice with viral vector-induced overexpression of α-synuclein in the substantia nigra were administered venglustat as food admixture. Motor and cognitive performance, α-synuclein-related pathology, and microgliosis were compared with untreated controls. Results: Venglustat worsened motor function in Thy1-aSyn transgenics on the challenging beam and the pole test. Although venglustat did not alter the cognitive deficit in the Y-maze test, it alleviated anxiety-related behavior in the novel object recognition test. Venglustat reduced soluble and membrane-bound α-synuclein in the striatum and phosphorylated α-synuclein in limbic brain regions. Although venglustat reversed the loss of parvalbumin immunoreactivity in the basolateral amygdala, it tended to increase microgliosis and phosphorylated α-synuclein in the substantia nigra. Furthermore, venglustat also partially worsened motor performance and tended to increase neurofilament light chain in the cerebrospinal fluid in the Gbadeficient model with nigral α-synuclein overexpression and neurodegeneration. Conclusions: Venglustat treatment in two mouse models of α-synuclein overexpression showed that glucosylceramide synthase inhibition had differential detrimental or beneficial effects on behavior and neuropathology possibly related to brain region-specific effects.

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