Polystyrene nanoplastics promote neurodegeneration by catalyzing TDP43 hyperphosphorylation

Winanto, Li-Yi Tan, Wai Hon Chooi, Cheryl Yi-Pin Lee, Wan Yun Ho, Yong Shan Lim, Boon Seng Soh, Emma Sanford, Chong-Lun Tan, Yih-Cherng Liou, Cathy Chia-Yu Huang, Shuo-Chien Ling, Shi-Yan Ng

Posted on: 8 January 2025

Preprint posted on 11 November 2024

The smoking gun: Plastic is harmful for your neurons

Selected by Manuel Lessi

Categories: cell biology, neuroscience, pharmacology and toxicology

A. Introduction

Every day, humans and wildlife are exposed to a huge number of environmental contaminants. Among these, plastic and its derivatives are now pervasive. A plethora of evidence has clearly established that plastic exposure is detrimental to human health in a variety of contexts and is linked to several disorders. Notably, polystyrene nanoplastics have been shown to cross the blood-brain barrier and exert toxic effects on the central nervous system, potentially leading to neurodegeneration and other neurological conditions.
In this study, the authors take advantage of the unparalleled flexibility offered by stem cells to investigate the effects of nanoplastics on stem-cell-derived neurons and mice. This led to the discovery of new molecular mechanisms through which plastic-derived contaminants hijack cellular processes to induce neuronal defects that resemble the neurotoxic phenotype observed in Amyotrophic Lateral Sclerosis (ALS).

B. Main Results

This paper tells a story and follows a logical sequence in presenting its results and how they came to be.

1. Can plastic enter neurons?

The first obvious question was: Can plastic particles enter neurons? While this may seem like a basic question, it is a fundamental one, as the entire study depended on the answer. To address this, the authors made clever use of fluorescently-labeled nanoplastic particles of different sizes. They showed that nanoplastics with a diameter of 50 nm can be easily internalized by neurons in both 2D cultures and 3D neurospheres.

2. Is plastic entry into neurons biologically harmful?

Once it was established that plastic can enter neurons, the second question arose: Does this cause any biological effects? The answer, unfortunately, is yes. Nanoplastics were shown to alter neural stem cell proliferation, reduce neuronal neurite length, and increase neuronal apoptosis after short exposure windows (24–48 hours). These findings suggest that plastic can interfere with key biological processes in neuronal cells, compromising their viability and functionality. This might explain why plastic exposure has been associated with neurotoxicity and neurodegeneration.

3. What are the mechanisms driving plastic-induced neurotoxicity?

The next question was: What biological mechanisms underlie the observed neurotoxicity? To answer this, the authors extracted cell lysates from cultured neurons, incubated them with polystyrene nanoplastics for half an hour, and examined the samples using mass spectrometry to identify proteins bound to the nanoplastics. More than 1,000 proteins were found to bind to the plastic, including key peptides implicated in Amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative diseases. These included well-established neurodegenerative hallmarks such as Tau and TDP-43.
Since around 9 out of 10 ALS patients exhibit TDP-43 dysfunction, including aberrant phosphorylation, the next step was to confirm whether TDP-43 plays a role in the neurotoxic effects observed. Indeed, exposing neurons to nanoplastics for 72 hours induced hyperphosphorylation of TDP-43, suggesting that TDP-43 phosphorylation is hijacked by nanoplastics which is likely responsible for pathological neurodegeneration.
All of these findings are extremely relevant and important as they advance our current understanding of the possible mechanisms altered by polystyrene contaminants in human neurons. Nevertheless, 2D neuronal cultures are far from being representative of the physiological complexity of in vivo biology. This is especially true for the nervous system, whose delicate physiology strictly relies on the complex cel-to-cell interaction among different cell types in time and space.

4. Are these results translatable to in vivo models?

Finally, the study addressed whether the in vitro findings could be replicated in a living organism. To answer this, adult mice were chronically exposed to polystyrene nanoplastics for two months. The results were striking: motor neurons in the ventral horns of the spinal cords of exposed animals were reduced in number and smaller in size. Additionally, nanoplastic exposure significantly increased the amount of aberrant TDP-43 isoforms in the spinal cords of these mice, a hallmark of ALS-based neurodegeneration.

C. Why I Highlight This Preprint

I found this preprint really interesting! The results are well presented, and the flow of information is seamless, making it an enjoyable, understandable, and highly informative read.
Taken together, the findings in this preprint highlight molecular mechanisms altered by polystyrene nanoplastics in neuronal cells, linking plastic exposure to neurodegenerative processes in both human-derived cells and mice. Considering that such contaminants are commonly found in food packaging and other everyday objects all of us encounter, these results are particularly alarming.
Beyond providing new evidence for a biological mechanism responsible for plastic-induced neuronal damage, these findings are of wider interest and relevance, especially in regulatory settings, as they prompt us all to minimize our exposure to plastic as much as possible.

D. Questions and Future Directions

While the results presented in this preprint are thoroughly validated and clearly link nanoplastic exposure to neurodegeneration, further experiments could deepen our understanding of the mechanisms involved:

1. Additional Layers of Profiling

Have you considered incorporating additional molecular analyses, such as RNA sequencing, or functional studies like electrophysiology, to further dissect the molecular cascades and functional phenotypes affected by nanoplastic exposure?

2. 3D Neural Models

While 2D cell cultures are instrumental in laboratory studies, 3D neural models better mimic the intricate pathophysiology of the nervous system. Have you thought about performing similar experiments using brain or spinal cord organoids? This could also help identify cell-type-specific effects, also in developmental settings.

3. Human Relevance of Exposure Levels

Plastic exposure has been linked to a spectrum of adverse outcomes in humans. How did you select the nanoplastic concentrations used in this study? Are these concentrations reflective of real-world exposure levels observed in human populations?

4. Therapeutic Potential

The results you present clearly show that nanoplastics drive neurodegeneration through TDP-43 hyperphosphorylation. Do you think there is potential for therapeutic interventions, such as blocking nanoplastic interactions or targeting TDP-43 to prevent its aberrant phosphorylation and restore a healthy neuronal phenotype?

Tags: ipsc, nanoplastic, neurodegeneration

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Author's response

Winanto shared

1. Additional Layers of Profiling

Incorporating advanced molecular analyses, such as RNA sequencing, will help to unveil transcriptional changes induced by nanoplastic exposure and elucidate broader molecular cascades. Although we have not performed RNA-seq in our current study, others have used this to understand the cellular processes in which nanoplastics disrupt biological processes. For example, Liang et al. (2022) utilized single-nucleus transcriptomics to reveal that polystyrene nanoplastics disrupt ATP metabolism, mitochondrial function, and proteostasis, particularly in neurons and astrocytes, leading to Parkinson’s disease-like neurodegeneration. Similarly, our findings showed that nanoplastic exposure reduce mitochondrial function in motor neurons. Our proteomic study reveals that nanoplastic can binds to proteins involved in neurodegenerative diseases such as TDP43 and result its hyperphosphorylation. To understand the exact mechanism as to how nanoplastics result in TDP43 hyperphosphorylation, we hope to perform in the near future in-silico molecular docking to visualize how polystyrene nanoplastics bring TDP43 and GSK3-b together to bring about hyper-phosphorylation of the former.

2. 3D Neural Models

In our current studies, RenVM 3D spheroids were used to understand the extent in which nanoplastic can potentially migrate into human neural tissues. Brain and spinal organoids are an exciting avenue to explore cell-type specific vulnerabilities to nanoplastics. Our lab has established a robust protocol to generate ventral spinal organoids (Hor et al., 2020) that contains not just motor neurons, but also other spinal interneurons, astrocytes, and oligodendrocytes. ALS is a disease in which glia cells are also implicated. The next step would be to use spinal organoids to deeply understand
whether nanoplastics affect each cell type differently in the CNS, and what this means for ALS pathogenesis.

3. Human Relevance of Exposure Levels

According to a 2019 study by WWF International, individuals may ingest up to 5 grams of plastic each week, equivalent to the weight of a credit card. This ingestion primarily occurs through microplastics present in drinking water and various food sources, with approximately 1,769 particles of plastic consumed weekly from water alone. While real-world consumption varies based on diet, lifestyle, and location, this estimate provides a benchmark for human exposure.
To link this to our experimental design, we calculated the particle concentration used in our study. We employed polystyrene nanoplastics at a concentration of 1.12 × 10¹² particles per milliliter and used 1 μL of this stock in 10 mL of media, resulting in a final concentration of 0.001%. This corresponds to approximately 1.12 × 10⁷ particles per milliliter in the experimental media. If we extrapolate these concentrations, the number of particles in our experiments reflects a plausible range of exposure, considering chronic human ingestion of microplastics over time.
Given the global increase in plastic use over the years, we also included a higher concentration of 0.01% (10 μL in 10 mL of media) to model potential future exposure scenarios. In our study, we observed a dose-dependent reduction in neuronal health, with higher nanoplastic concentrations exacerbating mitochondrial dysfunction, proteostasis disruption, and overall neurotoxicity. These findings suggest that increased nanoplastic exposure could have even more pronounced adverse effects on neural health. By bridging these concentrations, our study provides critical insights into the biological effects of environmental nanoplastics on neural cells and highlights the urgent need for mitigating plastic pollution.

4. Therapeutic Potential

The proteomic analysis in our study identified numerous neuronal proteins capable of binding to nanoplastics. However, targeting a single nanoplastic-protein interaction may not be sufficient to address the widespread disruptions to proteostasis in neurons. Additionally, targeting multiple kinases simultaneously, while potentially effective in reducing TDP-43 hyperphosphorylation, could inadvertently disrupt normal neuronal activity, leading to unintended neurotoxic effects.
As the saying goes, “prevention is better than cure.” We believe that reducing the use, consumption, and exposure to environmental micro- and nanoplastics is a more effective and sustainable approach than attempting to target specific protein interactions. This can be achieved through strategies such as implementing more stringent water purification processes. In our preliminary studies, co-treatment of nanoplastics with activated charcoal showed promising results, with improved neuronal survival and mitochondrial function. These effects are likely due to the ability of activated charcoal to sequester nanoplastics, thereby mitigating their harmful impact on neurons. This highlights the importance of proactive measures to reduce nanoplastic exposure while exploring complementary interventions to protect neuronal health.

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Polystyrene nanoplastics promote neurodegeneration by catalyzing TDP43 hyperphosphorylation

A. Introduction

B. Main Results

1. Can plastic enter neurons?

2. Is plastic entry into neurons biologically harmful?

3. What are the mechanisms driving plastic-induced neurotoxicity?

4. Are these results translatable to in vivo models?

C. Why I Highlight This Preprint

D. Questions and Future Directions

1. Additional Layers of Profiling

2. 3D Neural Models

3. Human Relevance of Exposure Levels

4. Therapeutic Potential

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Also in the cell biology category:

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Also in the neuroscience category:

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Investigating Mechanically Activated Currents from Trigeminal Neurons of Non-Human Primates

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