Understanding Heterogeneity In Parkinson’s Disease: A Tale Of Two Mice Strains

Parkinson’s disease is a debilitating neurodegenerative disorder, which majorly affects the elderly. Available scientific literature shows that genes, diet, and environment play an important role in its causation. Several neurological studies state that the Caucasians are relatively less-well protected against this disorder than the Asian-Indians.

Studies conducted in India at the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore by Dr. Alladi and team using human midbrains, donated at death and comparing them with the studies published in Western literature revealed that the midbrain dopaminergic neurons of the Indians are better endowed. Dopaminergic neurons are responsible for various aspects of movements. They are located in the midbrain region called ‘substantia nigra’ and degenerate in Parkinson’s disease. Surprisingly, the Indians had more of these neurons than the Caucasians. Further studies also revealed fewer degenerative alterations in them with normal age progression; while in the nigra of the Caucasians, the neurons die. The team was led by a neurologist Dr. Uday Muthane and included neuropathologists (Dr. Mahadevan, Dr. TC Yasha and Dr. SK Shankar) and a neurophysiologist (Dr. TR Raju).

‘Anglo-Indians’ are a mixed populace residing in India. The admixing is a result of the erstwhile colonial rule by different Western populations like the Portuguese, Dutch and the Britishers. It was more often that the male lineage was of the Colonial ruler i.e. the Caucasians and the female belonged to the ruled subjects i.e. the Asians-Indians. An epidemiological study by Ragothaman, Muthane, and colleagues showed a much lower occurrence of Parkinson’s disease in them. It has been hailed worldwide, that studying admixed populations is important to better understand the causative factors of any disease and to discover novel treatment strategies. However, studies on humans are not feasible to understand the deeper aspects due to availability and ethical concerns.

A recent study from Dr. Alladi’s lab, by doctoral students Vidyadhara D.J. and Yarreiphang H., in the Department of Neurophysiology at NIMHANS published in the journal Molecular Neurobiology, shines light on these mechanisms using experimental mice models. They took two distinct mice strains and drew parallels to different human populations. The disease condition was replicated in the mice using a neurotoxin MPTP, which is historically known for causing Parkinsonism in addicts. One of the mice types CD-1, showed very mild Parkinsonian features upon exposure to MPTP, whereas the other mice i.e. C57BL/6J was severely affected.

The F1 progeny have different coat colours. Majority (50%) of them have a brownish-grey coat whereas 25% are black and 25% are white. Coat colour does not affect the response to the neurotoxin. (Credit: Phalguni Alladi)

Using specialized staining techniques and advanced microscopy, they found that the midbrain of CD-1 mice possesses a larger number of dopaminergic neurons in the substantia nigra pars compacta.  An analogy can be drawn here between the human populations, where CD-1 is comparable to Asian-Indians and C57BL/6J to Caucasians, and their crossbreds would represent Anglo-Indians. Several other neuroprotective features like neurotrophic factor GDNF, along with Nurr-1 and PitX3 which maintain the health of the dopaminergic neurons were better protected in the MPTP-intoxicated CD-1. The study also reveals that ‘the size of the neuron’ which was considered as a trivial attribute may also be an important susceptibility factor. The difference was also seen in the striatum, an important brain area that is necessary for movement.

With these interesting findings, they further studied how admixture might be influencing Parkinson’s disease by crossbreeding and studying the offsprings when they reach adulthood. To their surprise, brain features of crossbreds were augmented, better than both the parent mice strains. MPTP failed to have any toxic effect on the dopaminergic neurons of the admixed mice. In fact, they revealed enhanced resilience in various parameters than even CD-1. They envisage that similar neural attributes of resilience may be responsible for lower susceptibility in the Anglo-Indian population. Thus, this study provides scientific evidence for heterogeneity amongst ethnicities to develop Parkinson’s disease and the perspective of transmission of genetic vigor following admixture.

Why Are These Studies Exciting?

These attributes that apply to the different ethnic populations may also answer an important question as to “why within populations certain individuals are more likely to suffer from a disease”? These kinds of studies can be performed to understand the susceptibility parameters in other diseases too. The minimum need would be to identify the correct brain regions and the appropriate mice strains.

Is There A Word Of Caution?

Yes. Admixing may not always be beneficial. Here, the baseline vulnerability of the parent strain may be the all-important criteria for transmission of genetic vigor. Two susceptible individuals may not necessarily bring a protected off-spring. Future studies at NIMHANS, India are being directed to dissect out other molecular aspects and understand the disease process in a greater detail.

These findings are described in the article entitled Admixing of MPTP-Resistant and Susceptible Mice Strains Augments Nigrostriatal Neuronal Correlates to Resist MPTP-Induced Neurodegeneration, published in the journal Molecular Neurobiology. This work was led by Phalguni Alladi from the National Institute of Mental Health and Neurosciences.