A Mouse Model to Test Novel Therapeutics for Parkinson's Disease: an Update on the Thy1-aSyn (“line 61”) Mice

Abstract

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.

Double‐Edged Effects of Venglustat on Behavior and Pathology in Mice Overexpressing α‐Synuclein

“…In Thy1-aSyn mice, α-synuclein aggregation and microgliosis coincide with progressive development of motor and nonmotor symptoms, supporting its frequent choice for preclinical studies. 20 Thy1-aSyn mice develop manifest parkinsonism with loss of striatal dopamine and L-dopa-responsive deficits at 14 months of age. 23 At 1 to 6 months of age used in this study, Thy1-aSyn mice represent a model of premanifest PD.…”

“…Thy1-aSyn (line 61) transgenic mice overexpressing human WT α-synuclein under the Thy-1 promoter were maintained on a mixed C57BL/6-DBA/2 background as described previously. 18,20 Polymerase chain reaction amplification analysis was performed on ear tissue samples collected both at birth and at the completion of the experiment. Only mice with confirmed genotypes were included in the analyses.…”

“…In parallel to the MOVES-PD trial, we had tested venglustat as a potential benchmark in a mouse model with overexpression of human wild-type (WT) α-synuclein under the murine Thy-1 promoter (Thy1-aSyn mice, Masliah-line 61). [18][19][20] Thy1-aSyn mice recapitulate key features of PD, such as α-synuclein pathology, dopamine loss, microgliosis, and a slow progressive prodromal phase with motor and nonmotor symptoms. [21][22][23] This PD model has been used extensively for preclinical efficacy studies of drug candidates.…”

A New Look at Animal Models of Neurological Disorders

“…Since the discovery of the role of alpha-synuclein in these disorders through human genetics and pathology, animal models based on the expression of the protein have supplanted previous toxinbased models which only reproduced the end point of the pathological process, the death of dopaminergic neurons, rather than the pathological process. Extensive animal studies are beginning to clarify the contribution of various forms of alpha-synuclein to the pathology (Peelaerts and Baekelandt [5]), to elucidate the mechanisms of disease spread first suspected on the basis of human postmortem pathological studies (Pinto-Costa et al [6]), and to model previously neglected non-motor aspects of Parkinson's disease (as reviewed by Richter et al [7]). Furthermore, Stefanova [8] shows how genetic manipulations in mice led to the generation of a model of Multiple Systems Atrophy, a rare disease in which alphasynuclein surprisingly accumulates in glial cells rather than in neurons.…”

“…Furthermore, Stefanova [8] shows how genetic manipulations in mice led to the generation of a model of Multiple Systems Atrophy, a rare disease in which alphasynuclein surprisingly accumulates in glial cells rather than in neurons. Each of these models contributes to a better understanding of synucleopathies, and some provide meaningful tools for the preclinical testing of novel therapies [7,8]. In the absence of a neuroprotective treatment that has been validated in the clinic, their predictability remains uncertain.…”