Animal models of synucleinopathies and how they could impact future drug discovery and delivery efforts

ABSTRACT

Introduction: Ample efforts have been carried out to develop efficient disease-modifying drugs of Parkinson’s disease and related synucleinopathies. At present, the available animal models appropriate for drug development and delivery for these hitherto incurable disorders are limited.

Areas covered: The author, herein, provides their perspectives on classical toxin-based animal models, which have provided some insight into their clinical picture and complex pathogenesis. They also discuss generic and virus-induced models and more recent αSyn transmitter models that reproduce essential clinical and morphological aspects but do not fully replicate the whole spectrum of the human diseases. Yet, these models have, however, provided new insights into the pathogenesis of these disorders.

Expert opinion: The recent development of transgenic viral vector-induced αSyn inoculation models and those using induced pluripotent stem cells (iPSCs) in rodents, non-human primates and (rare) primates, reproducing many but not all aspects of the human synucleinopathies and their complex pathogenesis opened the door for the development of successful drugs. Despite these limits, a remarkable amount of work has already been done. However, further attention should be focused on the development of new models to enable better insight into the pathology of these proteinopathies as the basis for the future development of real disease-modifying or even preventive modalities.

KEYWORDS:

• Animal models
• Parkinson’s disease
• multiple system atrophy
• synucleinopathy
• impact for future therapy

Article highlights

• Synucleinopathies, a heterogenous group of progressive neurodegenerative disorders caused by misfolded α-synuclein (αSyn) proteins, includes Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, the pathogenesis of which is poorly understood, and treatment options are still limited.

• Pharmacologic-toxic and generic animal models have contributed to a better knowledge of the pathogenesis of these disorders and their major clinical features, although none of them covered the whole aspects of human disease.

• New transgenic viral-induced models, those using pluripotent stem cells (iPSCs), and, in particular injection of preformed αSyn fibrils into the brain of non-human primates and primates, reproducing many but not all morphological and clinical aspects of the human proteopathies and their complex pathogenesis, have provided worthful insights into their pathobiology as a basis for the development of novel, possibly disease-modifying therapies.

• Further studies of the transmission and spreading of αSyn strains may promote the development of new biomarkers for early diagnosis and better elucidation of disease progress.

• Since the pathogenesis of Parkison disease and related synucleinopathies is not caused by a single but multiple factors, it seems impossible that a single treatment can help and stop the progressive neurodegeneration. Thus, a combination of drugs and treatment options will be necessary, that could be developed by the combination of novel models.

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Declaration of interest

The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The author is supported by the Society for Support of Research in Experimental Neurology, Vienna, Austria.