Neuroscience in the News

The etiology of idiopathic Parkinson’s Disease (PD) is not well-studied. PD is commonly thought to have
resulted from the loss of connectivity within the cognitive circuits, but we are not sure about the neural
substrate and the mechanism that caused the progression of the disease. An existing hypothesis based on
human postmortem study states that α-synuclein (α-syn) pathology could spread from gut to brain via the
vagus nerve and kill dopamine neurons of the substantia nigra pars compacta (SNc), which would result
in the aforementioned circuit dysfunction (Braak et al., 2003, 2004). However, it hasn’t been tested well
experimentally.

Previous studies utilized injection of preformed fibrils (PFF), a principal component of Lewy Bodies
(LB), into the striatum (STR) of mice to investigate the mechanism of transmission of the fibril forms of
α-syn (Luk et al., 2012; Mao et al., 2016). However, it doesn’t well describe PD’s features because there’s
rarely LB pathology observed in STR.

Therefore, a new model is implemented to fill in the gap by mimicking the spread of pathologic α-syn
observed in PD using the injection of PFF to the duodenal and pyloric muscularis layer (Kim et al., 2019).
The study uses multiple experimental methods to investigate the following problems, which altogether
suggest that the proposed model of propagation of pathologic α-syn from the gut to the brain can model
PD (Kim et al., 2019).1

1. The hypothesized gut-to-brain transmission of pathologic α-syn

Gut-to-brain spread is tested by injecting PFF into pylorus and duodenum, with pSer129-α-syn
immunostaining as a tool to monitor the progression of pathologic α-syn. Comparison between the
treatment and control groups showed significant differences in the DMV2 in MO3 and LC4 at first and then
in the amygdala, VMB5, HIP6, and PFC7. The results from immunohistochemistry and quantitative
analysis are confirmed by immunoblot analysis, supporting the gut-to-brain transmission hypothesis.

1
#NeuralSubstrate: As a background of the study, explained clearly how the physiological substrate a-syn
can spread across the body and influence dopamine levels, therefore impact connectivity within cognitive
circuits, giving rise to PD. Explained how this chain would inform the experiment design and gap in
current understandings.
2
DMV: dorsal motor nucleu
3
MO: medulla oblongata
4
LC: locus coeruleus
5
VMB: ventral midbrain
6
HIP: hypothalamus
7
PFC: prefrontal cortex
 2. Whether pathologic α-syn causes dopamine neuron degeneration

After the PFF injection into the PS and UD, stereologic methods were used to monitor TH- and
Nissl-positive cell counts, indicating a significant loss of DA neurons in the SNc. The results are
consistent with the reduction of other chemicals like the striatal DA metabolites, tested by
High-performance liquid chromatography (HPLC) which is confirmed by single photon emission
computed tomography (SPECT)/computed tomography (CT).

3. Whether pathologic α-syn causes PD-like motor and non-motor symptoms

Motor and non-motor symptoms like cognitive and behavioral deficits are assessed by multiple tests like
Morris water maze task and nest building test, with results showing that injection of α-syn PFF causes the
PD-like symptoms.

4. Whether truncal vagotomy could prevent the gut-to-brain spread of α-syn and associated
neurodegeneration and behavioral deficits.

Truncal vagotomy was conducted on wild-type (WT) mice after PFF/PBS injection which is compared
with the non-TV groups, showing non-detection of pathologic α-syn in TV mice, supported by
dopaminergic and behavioral results.

The study uses multiple lines of evidence to test the hypothesis. To test the overarching hypothesis, the
study proved the capability of pathologic α-syn to spread from gut to brain, tested PD-related DA
degeneration and assessed motor and non-motor symptoms given the gut injection, which all aligned with
the clinical features of PD. Complementary methods added credibility to the proposed mechanism that it
not merely correlates with the progression of PD but is more likely to be a good explanation.

The study used converging approaches to test each sub-hypothesis. For example, to test for the DA
neurons, we measured DA concentrations in both groups by HPLC over time, DAT with SPECT/CT
scans, and quantified the results. SPECT/CT scans provide a structural image and highlight the spatial
configuration of DA concentrations while the quantified result allows for direct comparison and test for
significance. Measuring for both DA and DAT complements each other and increases credibility.
In the experiments, the subjects were randomized and mixed-gender, with acclimatization process and
genotyping process in place to remove potential confounders. Other confounders like food intake were
also controlled. Uncertainty is minimized by injecting it into four different locations of the gut.

Statistical significance was assessed via ANOVA test with a significance level of p < 0.05. To ensure the
reliability of the result, all data collected are pre-registered and published, and researchers are blinded to
the treatment group during the experiments. Potential ethical issues like animal subjects were also
discussed.8

Although the study is very comprehensive, limitations remain that experiments on mice cannot fully
simulate the human body. Therefore, it might be beneficial to combine with lesion studies or
immunohistochemistry studies for existing PD patients to further support the hypothesis. It’s also
necessary to acknowledge that there may exist other mechanisms other than from the gut that spread
pathological α-syn to the brain, therefore it might be necessary but not sufficient. Further studies need to
be done to understand the mechanism.9

Overall, the study advances the previous research and offers an explanatory model for the progression of
PD which has great implications for future treatments and research.

The news article published by the Guardian (Davis, 2019) is a great presentation of the research for the
non-expert audience. The author described the findings with the appropriate level of accountability,
highlighting that the paper provided credible experimental evidence while acknowledging the limitations.
She explained relevant terminologies like α-synuclein and its mechanism as background information,
making it easier to understand. The article also used colloquial words like ‘misfolded α-syn’ instead of
‘pathologic α-syn’ to increase the readability. Interviews with the researchers also helped to highlight the
importance of the research and its relevance to the audience’s daily life. For example ending upon the
implication of disease prevention would further engage the audience.

WORD COUNT: 897

8
#ss152-NeuroscienceApproaches: evaluated how converging approaches (behavioral tests, structural
imaging techniques, chemical measurements) complement each other and together fulfill the causal chain
and support the overarching hypothesis.
9
#ss152-CritiqueExpDesign: Explained the adopted experimental design and the benefits and limitations
of such a design and underlying measures. Conducted critique on the experimental design and offered
suggestions.
 References

Braak, H., Del Tredici, K., Rüb, U., De Vos, R. A., Steur, E. N. J., & Braak, E. (2003). Staging of brain
pathology related to sporadic Parkinson’s disease. Neurobiology of aging, 24(2), 197-211.

Braak, H., Ghebremedhin, E., Rüb, U., Bratzke, H., & Del Tredici, K. (2004). Stages in the development
of Parkinson’s disease-related pathology. Cell and tissue research, 318(1), 121-134.

Davis, N. (2019, June 26). Growing evidence suggests parkinson's disease starts in gut. The Guardian.
Retrieved October 5, 2022, from
https://www.theguardian.com/society/2019/jun/26/growing-evidence-suggests-parkinsons-di
sease-starts-in-gut

Kim, S., Kwon, S.-H., Kam, T.-I., Panicker, N., Karuppagounder, S. S., Lee, S., Lee, J. H., Kim, W.
R., Kook, M., Foss, C. A., Shen, C., Lee, H., Kulkarni, S., Pasricha, P. J., Lee, G., Pomper,
M. G., Dawson, V. L., Dawson, T. M., & Ko, H. S. (2019). Transneuronal propagation of
pathologic α-synuclein from the gut to the brain models parkinson’s disease. Neuron, 103(4).
https://doi.org/10.1016/j.neuron.2019.05.035

Luk, K. C., Kehm, V., Carroll, J., Zhang, B., O’Brien, P., Trojanowski, J. Q., & Lee, V. M. Y. (2012).
Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in
nontransgenic mice. Science, 338(6109), 949-953.

Mao, X., Ou, M. T., Karuppagounder, S. S., Kam, T. I., Yin, X., Xiong, Y., ... & Dawson, T. M. (2016).
Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science,
353(6307), aah3374.