Naturally Occurring Parkinson’s Disease Raises the Need for Nonhuman Primates in Neurodegenerative Diseases Research

Parkinson’s disease (PD) is a common neurodegenerative disorder that affects millions of people [1]. Typical symptoms of PD include bradykinesia, rigidity, resting tremor, and postural instability [1]. Therefore, PD severely affects the patient’s daily life and mental health and imposes a tremendous burden on the medical system. In the past few decades, numerous studies have uncovered pathogenies and developed therapies for PD. However, the disease-modifying treatment of PD is still a major challenge worldwide. One of the important reasons is that most of the basic research on PD have not directly studied patients with PD but used animal models [2]. It is believed that PD is a human-exclusive disease because it has not been identified in other animals, including nonhuman primates [3]. Rodent PD models created by toxins including 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or gene-editing only imitate some symptoms of PD but do not fully replicate the pathogenies including the neuronal loss in the substantia nigra (SN) [4]. Thus PD is considered to be a consequence of human brain evolution that the dramatic expansion of neocortex creates a significant burden on subcortical circuits [3].

Under this circumstance, from the point of view of evolution, there is another possibility: that PD is evolving concurrently in other primates (nonhuman primates, NHPs) given their genetic similarity. The fact that no NHPs with PD have been identified cannot rule out the possibility that PD is naturally occurring in a small portion of NHPs without being noticed.

To answer this question, very recently, a group of Chinese researchers, Li et al. carefully screened a large population of monkeys at the Kunming Primate Research Center and attempted to identify those with naturally-occurring PD [5]. By using various criteria including clinical symptoms, pharmacological responses, pathological evidence, and genetic mutations, a 10-year old male cynomolgus monkey without any operation was diagnosed as having PD. The monkey showed four lines of evidence and got a PD score over 15 out of 20 on the rating scale. The score indicated that the monkey had severe PD symptoms including bradykinesia, tremor, and postural instability, which are all typical PD symptoms. The pharmacological test on the monkey was positive, showing that the PD score decreased significantly after taking levodopa (a commonly used drug for PD). Treatment with apomorphine was also effective in lowering the PD score. Pathologically, Li et al. found that the monkey had a severe loss of dopaminergic neurons in the SN, which is the pathological hallmark of PD [1]. Although the study did not find Lewy bodies (another pathological hallmark of PD) in the monkey, it found alpha-synuclein, which is the early stage of the Lewy body [1]. The study also found an increased number of microglial cells and astrocytes in the monkey, which serves as further pathological evidence of PD. Besides, the study ran a sequence analysis and found that the potential cause of PD in the monkey was a missense mutation in LRRK2 [2]. These together clearly indicate that this monkey had PD. Thus, a spontaneously-occurring PD monkey has been identified.

This is the first report of a naturally-occurring PD monkey in the world. The finding indicates that PD is not a exclusively human disease but developed before the speciation of humans. As a close relative to humans, a monkey can spontaneously develop an animal version of PD that is very similar to humans in symptoms, pathology, and genetic mutations. Therefore, the monkey is an ideal candidate for PD research and therapeutic strategy development.

Previously, rodents were widely used in basic and translational studies of PD regardless of the tremendous differences between rodents and humans. However, no report has ever claimed that rodents can naturally develop PD, suggesting that the mechanism in these two species could be different (Fig. 1). Even though many strategies to treat PD have been developed based on rodent studies [6], the chance they can be successful in treating patients with PD would be low. Therefore, the focus of PD studies, including the evaluation of PD biomarkers [7], should move to NHPs given they are more genetically and anatomically close to humans, have very similar symptoms and pathogenies, and can develop PD spontaneously [5]. The successful identification of monkeys with naturally-occurring PD also suggests that other neurodegenerative disorders such as Huntington’s disease (HD) [8] and Alzheimer’s disease (AD) [9] may also naturally occur in NHPs. Extra screening of a large population of NHP is needed to clarify this possibility.

Fig. 1.

The advantage of the monkey model in PD research. In addition to the similarity to PD patients in clinical symptoms, pharmacological responses, pathology, and genetic mutations, the monkey model can spontaneously develop PD, which has never been reported in rodent models.

What was missing from Li et al.’s study was that the authors could not trace back the history of the PD monkey’s family. Although they found the LRRK2 mutation in the PD monkey, it is still difficult to claim that PD is caused by a particular gene mutation or environment. Other than the hypothesis that PD is the consequence of human brain evolution [3], it is time to establish a new hypothesis regarding the presence of PD in humans.

In general, using NHPs as research models, there will be a higher chance of generating new theories and develop new effective therapeutic strategies for PD and other neurological disorders including HD and AD. To push the research to transmit from rodents to NHPs, a close collaboration is urgently needed across the scientific community, pharmaceutical corporations, governments, and evaluation systems including academic journals [10]. For example, research funds should shift towards NHPs, and academic journals should consider publishing more NHP-related studies. We hope to see that human patients with neurodegenerative diseases could eventually benefit from NHP research in the foreseeable future.

Conflict of interest

The authors declare no competing interests.