From Myelin Loss to Memory Decline: How Chronic Cellular Stress Drives Neurodegeneration

 Pelizaeus-Merzbacher disease (PMD), is a rare neurological disorder that disrupts myelin in the brain. A mutation in the PLP1 gene affects oligodendrocytes which are the cells that produce myelin. When PLP becomes mutated, it results in a build up inside the cell and stress becomes a factor in the endoplasmic reticulum. To counteract the stress, the body has an integrated stress response (ISR) to protect itself from any harm. In PMD, the ISR is activated for longer than it needs to be and ends up doing more harm than good which ends up killing the cells its supposed to protect. As oligodendrocytes die, myelin production stops and the brain enters a state of hypomyelination. In a study by Yanan Chan et al., researchers used a mouse model to discover, that deleting a protein named PERK reduced ISR activity. This resulted in the mice living two weeks longer with improved myelination. Over working the ISR can do the opposite of what its supposed to and actually drive the progression of disease.

On the contrary, Alzheimer's diseases isn't caused by myelin loss, instead its caused by damage to the hippocampus resulting in memory loss. During a study by Sabitha, K.R. et al., researchers used advanced single-cell techniques to show that the human brain can still generate immature neurons even in a disease state. One specific neuron, CA1, shows early changes in gene activity before any significant damage is visible. Disease isn't something that happens spontaneously, it is a slow build up of molecular changes that weaken memory circuits over time.

What connects the two studies is chronic cellular stress. In PMD, the ISR is supposed to playing a supportive role but instead does the oppoistire once its played its part for too long resulting in making the progression of disease quicker. In Alzheimer's disease, stress that accumulates over time slowly destroys the hippocampus and can't be seen until enough is lost. In both diseases, the damage starts at the molecular level. In PMD's case its myelin loss and in Alzheimer's it is the buildup of plaque. Understanding the shift of when molecular process are disrupting instead of helping would be key in slowing the development of neurodegeneration.

Chen, Y., Kunjamma, R.B., Lin, K. et al. Integrated stress response inhibition prolongs the lifespan of a Pelizaeus-Merzbacher disease mouse model by increasing oligodendrocyte survival. Nat Commun 17, 1285 (2026). https://doi.org/10.1038/s41467-025-68045-0

Disouky, A., Sanborn, M.A., Sabitha, K.R. et al. Human hippocampal neurogenesis in adulthood, ageing and Alzheimer’s disease. Nature (2026). https://doi.org/10.1038/s41586-026-10169-4

Why have there not been any cures for oligodendrocyte-related diseases?

 I had the privilege to attend a neuroscience seminar where Dr. Yanan Chen spoke about her research on Pelizaeus-Merzbacher Disease and oligodendrocyte survival. Due to my interest regarding the topic of hypomyelinated neuronal diseases, I made the decision to research and learn more about it and discuss my findings. Because there is little to be known about the direct causes of Multiple Sclerosis and, therefore, finding a cure, I find it interesting to learn about other similar diseases, such as PMD, that affect the myelination process. Dr. Chen’s research and other studies, however, are changing this by showing possible solutions or resistance therapies to these diseases. 

Before presenting her findings and research during the NEUR 300 seminar, Dr. Yanan Chen presented a study that shows how Pelizaeus-Merzbacher Disease negatively impacts the survival of oligodendrocytes and how integrated stress response inhibitors can aid in preserving the oligodendrocytes’ survival, despite the effects of PMD. They focused mainly on the male PMD mouse model Jimpy to “determine the impact of integrated stress response (ISR) on the oligodendrocyte response to mutant PLP expression” (Chen 2025). The study found that when the ISR-triggering eukaryotic initiation factor (eIF) 2α kinase was successfully inactivated, this process correlates with the survival of oligodendrocytes and myelination in the CNS. 

I became interested in this particular study because, when doing my own research, I found that I knew from previous research and courses at Loyola University Chicago that Multiple Sclerosis was a similar disease in the sense that it involves hypomyelination of axons, and therefore, I was wondering why there was not a cure yet found for either disease. I found a supplementary study by Doghish, Elazazy, Mohamed, Mansour, Ghanem et al. (2023), that describes how miRNAs could possibly play a significant role in Multiple Sclerosis "pathogenesis, diagnosis, and therapeutic resistance", and I was immediately intrigued (Doghish 2023). The study revealed that the diagnosis of Multiple Sclerosis was difficult “due to the lack of disease-specific biomarkers” and therefore, depends on ruling out numerous disabilities (Doghish 2023). Because of this, the researchers hope to further study “biological features of miRNAs in MS and explore their potential as a therapeutic target” (Doghish 2023). 

When reviewed as a whole, these investigations only provide a broad and hopeful conclusion to the problem, however, more research and findings must be done to provide a convincing conclusion overall. While Dr. Chen showed that the ISR-triggering eukaryotic initiation factor (eIF) 2α kinase was completely non-functioning, the survival of the oligodendrocytes and myelination of the CNS increased, Doghish, Elazazy, Mohamed, Mansour, Ghanem et al. (2023) showed that there is much to be revealed in the future regarding the future of miRNAs in multiple aspects of MS. These new discoveries and sciences may be used to treat not only PMD and MS, but also, provide a different approach to diagnosing and treating diseases involving the structure and functionality of the CNS. Together, these investigations reveal a bridge between neurological understandings and discussion, and therefore, provide hope for the future of curing uncurable diseases. 

 

References: 

Chen, Y., Kunjamma, R.B., Lin, K. et al. Integrated stress response inhibition prolongs the  lifespan of a Pelizaeus-Merzbacher disease mouse model by increasing  oligodendrocyte survival. Nat Commun (2025). https://doi.org/10.1038/s41467- 025-68045-0  

Doghish, Ahmed S, et al. “The Role of MiRNAs in Multiple Sclerosis Pathogenesis,  Diagnosis, and Therapeutic Resistance.” Pathology, Research and Practice, vol.  251, 1 Nov. 2023, pp. 154880–154880, https://doi.org/10.1016/j.prp.2023.154880.  Accessed 19 Apr. 2024. 

Nature and Nurture in Neurohealth

Today, people rely on their 5 senses to see the beauty of nature and life. The sense of sound is essential in listening to music, people, and the world around them to be able to make everlasting memories. Sound is, however, more than mere hearing; it is the precursor to overall health and function of the brain. What if auditory processing can be identified for neurological health in people whether genetically or man?

 Not long ago I had the opportunity to listen to Dr. She worked to determine whether concussions could be identified in children through brain responses to sound. Krizman’s research on concussions was aimed at identifying if brain responses to sound were identification of concussions in children (Krizman, 2023) by studying fundamental frequency (FO), “also known as the pitch cue”, and the frequency following response (FFR) and its effects on auditory processing following a concussion. One of the first observations was the effect of concussions on neural timing. A concussion therefore hampers the coordinated firing of neurons, which constitutes sound encoding. Brain responses are desynchronized, signals are dispersed, and arranged electrophysiological potentials of pitch have reduced efficacy. Finally, in those who have had a concussion, the auditory brainstem encoding of sound was tested by looking at FFR. There was a weakening of the F0 pitch, reduction of the response, and less accurate tracking of the sound in response to stimuli. In summary, concussions have adverse effects on the subcortical encoding of information, and this understanding can be a focal point in identifying injury or recovery.

A Neuroscience-based research study I came across, “Neural coding of formant-exaggerated speech and nonspeech in children with and without autism spectrum disorders” by Chen et al. Specifically, the TD children and children with ASD underwent testing of neurophysiological encoding of speech sounds at the neural level through a mechanism known as the frequency following response (FFR). The first conclusion was that children with ASD lacked automatic neural enhancement of exaggerating their speech compared to TD children. An exaggerated speech in TD children resulted in a better neural response, and the brainstem response was more accurate than in children with ASD whose neural response did not increase significantly and there was no brainstem response to enhancement. This reflects the influence on the cortex, which normally makes for its enhancement towards the brainstem responses to meaningful speech. In ASD children, the lack of enhancement meant speech was neurologically prioritized differently than in TD children. Finally, this can have a downside effect on the language development of children with ASD. From the neural differences, research can point towards early sensory contributions to language and differences in communication when it comes to autism.

While Dr. Krizman’s study focused on an injury and Dr. Chen’s was developmental, both studies demonstrated how the auditory system can be susceptible to disruption in the brain, leaving speech processing vulnerable. In concussed children, there was delayed neural timing in the brainstem that affected the encoding of speech, and in ASD children, their exaggerated speech was not able to lead to the neural enhancement experienced by TD children due to their altered use of the cortex. Ultimately, this shows a neurodevelopment comparison to neurotrauma and its effects in areas of the brain, leading to implications. This can then potentially be used to catch indicators of neurological health

Kraus, N., Thompson, E. C., Krizman, J., Cook, K., White-Schwoch, T., & LaBella, C. R. (2016). Auditory biological marker of concussion in children. Scientific Reports, 6(1). https://doi.org/10.1038/srep39009

Chen, F., Zhang, H., Ding, H., Wang, S., Peng, G., & Zhang, Y. (2021). Neural coding of formant‐exaggerated speech and nonspeech in children with and without autism spectrum disorders. Autism Research, 14(7), 1357–1374. https://doi.org/10.1002/aur.2509

The Hidden Impact of Concussions

A concussion is often characterized as a temporary brain injury associated with headache, dizziness and memory problems; however emerging neuroscience research has suggested that it has evident effects on the brain's ability to process sound and speech, extending beyond the anticipated symptoms. More specifically, causing difficulty in listening and communicating which possesses the question if hidden symptoms of brain injuries and often explained away by fatigue and distraction?

A few weeks ago I had the opportunity to listen to Jennifer Krizman’s presentation on the auditory biological markers of concussion in children, where she discussed how concussions impact the way the brain processes speech. She studied frequency following response, which captures how accurately the brain responds to sound. Her presentation and emergent dissolves suggest that concussion can have a more significant effect on the sensory processing system compared to traditional symptom-dependent diagnoses. 

Similar findings are studied in a recent study tilted Persistent post-concussion symptoms include neural auditory processing in young children which explained how concussions influence auditory processing after initial symptoms seem to improve. The researchers found that children with concussions have weaker neural encoding of speech sounds, specifically for pitch-related cues which are integral in unders†ådning everyday speech. These findings support Kriman’s idea that the effect of concussion can still be present in the brain after symptoms seem to improve, which indicates recovery can not be solely judged by symptom reports.

How Hands Help and Hurt

 When we think about learning, we usually focus on what is said. We assume that words carry the meaning and that gestures are just extra movement. But research in cognitive science suggests that our hands may play a much larger role in comprehension and memory than we realize. Research in cognitive science shows your hands shape, meaning, and memory. Gesture shifts comprehension. Gesture also disrupts comprehension. Natalia Zielinski and Elizabeth Wakefield tested this in 2021. They studied Polish-English bilingual children. They asked one question. Do gestures help more when language feels harder? 

Children watched stories in English and Polish. English served as stronger language. Polish served as weaker language. The storyteller used two gesture types. Matching gestures reinforced speech. Mismatching gestures added unstated details. Researchers tracked eye movement. They measured recall after each story. The results showed patterns. Children recalled more when matching gestures paired with weaker language. They looked at their hands more during weaker language. Gestures worked as support. When speech strained processing, children shifted attention to visual input. Mismatching gestures failed to help. Some reduced accuracy. 

Nicole Dargue found similar effects. Gestures aligned with speech improved comprehension. Gestures misaligned increased cognitive load. Cognitive load drives this pattern. Working memory holds limited information. Adults store about four chunks at once. Second language processing consumes capacity. Matching gestures distribute information across visual and verbal systems. Mismatching gestures demand integration of extra content. Capacity overload reduces recall. 

Zielinski’s eye-tracking data explains the mechanism. Attention shifts are based on difficulty. Gesture helps when you allocate focus. Gesture fails when attention splits. 

When you teach or present, do your hands mirror your words? Or do they introduce new content? In bilingual classrooms, gesture choice shapes equity. Students learning in a weaker language benefit from aligned visual cues. Extra motion without alignment strains memory. 

You communicate every day. When content grows complex, where do your eyes move? 
When you speak, do your gestures support your message or compete with it? 

References

Dargue, N., & Sweller, N. (2020). Learning stories through gesture: Gesture’s effects on child and adult narrative comprehension. Educational Psychology Review, 32(1), 249–276.

https://doi.org/10.1016/j.ridd.2021.104000

Zielinski, N., & Wakefield, E. M. (2021). Language proficiency impacts the benefits of co-speech gesture for narrative understanding through a visual attention mechanism. Proceedings of the Annual Meeting of the Cognitive Science Society, 43.

(02.03.26) - Elizabeth Wakefield - OneDrive