Animal models of Parkinson’s: from worm to rodent

A large body of research has focused on creating an animal model of Parkinson’s which will allow researchers to understand the disease better and identify potentially disease modifying therapies. Although no model to date succeeds in capturing all of the diversity of Parkinson’s, both in terms of symptoms and changes in the brain and body, each has its strengths. Thanks to technological and scientific advances particularly in the realm of genetics, new insights from newer and better models can be anticipated.

The cause of Parkinson’s remains unknown, but evidence suggests that there is an important genetic component. Several genes have been identified including the gene for alpha synuclein, SNCA, one of the most important pathological hallmarks of Parkinson’s, LRRK2, which codes for enzymes that modify many proteins in cells, PINK1 and Parkin/PARK2 involved in controlling the function of mitochondria and degrading damaged ones appropriately, and GBA involved in handling lipids inside the cell which are necessary for the formation of membranes and neurotransmission. These are to date the most common genetic risk factor for Parkinson’s.

This work brings together a vast body of work on animal models, which have addressed the effects of different genetic changes involving each of these genes in an effort to recreate Parkinson’s. This work in animals is important and necessary because it can allow us to study molecular and chemical changes that could shed light into what causes Parkinson’s in people and, in turn, what might slow, stop or reverse it.

The authors review research efforts in a range of organisms, including the roundworm (C elegans), fruit fly (Drosophila), zebrafish, mice and rats, as well as non-human primates. They outline the strengths and weaknesses of each of these models in terms of whether genetic manipulations succeed in recreating features seen in people with Parkinson’s. The more faithfully these can be replicated, the greater the potential of findings in these models to actually bear fruit in humans.

In this detailed piece, the authors address first of all how each model performs in terms of whether it succeeds in exhibiting 1) alpha synuclein build up, 2) neurodegeneration and loss of dopamine that mimics that seen in people with Parkinson’s, 3) motor symptoms such as slowness of movement and difficulty walking, and 4) non-motor symptoms such as memory, digestive and sleep problems. They conclude that while no existing model succeeds in capturing perfectly all of these diverse manifestations of Parkinson’s, simpler organisms such as the roundworm, fruit fly and zebra fish are more consistent in succeeding in reproducing alpha synuclein accumulation, neuron loss (albeit in much simpler nervous systems) and some motor symptoms. Reasons underlying inconsistent results in other organisms may be the specific genetic methods used, but also simpler issues like the need for the experimenter to interact with the experimental animal during assessment, which could obscure behavioural symptoms. Newer techniques and technologies are coming into play, which address these issues head on, so significant progress in terms of ensuring consistency is on the horizon.

The authors call for the systematic and complete characterisation of new animal models, and should include motor and non-motor symptoms, as well as alpha synuclein, neuron and dopamine loss, so that published work is complete and comparable from now on. They also call for publication of negative findings, that is, experiments which fail, which normally don’t make it to print. It is essential for these efforts to be streamlined.

• https://www.parkinsonsmovement.com/alpha-synuclein-roadmap/
• https://www.parkinsonsmovement.com/neurotrophic-factors/
• https://www.parkinsonsmovement.com/nly01/