How Can Human Neural Models Better Support Development and Disease Research?

Questions for Dr. Sandrine Da Cruz

Translational Relevance and Long-Term Neurodegenerative Disease Modeling

Question from the audience
How do such models translate to patients with progressive neurodegenerative diseases?

Dr. Da Cruz’s answer
These models provide mechanistic insight and enable patient-specific perturbations (e.g., genetics, environment), but translation still relies on converging evidence across systems. We combine human cellular assays as well as in vivo systems to increase robustness of our findings. Their strength lies in identifying early and disease-dependent dysregulated vulnerabilities that can inform biomarkers and therapeutic targets, which can ultimately be validated in patients.

Question from the audience
What are the main challenges in the long term study of neurodegenerative diseases?

Dr. Da Cruz’s answer
Key challenges include maintaining mature, stable phenotypes over time, modeling aging, capturing slow disease trajectories, and preserving multicellular interactions (e.g., glia, immune components). Recapitulating disease heterogeneity are also challenging, yet tremendous progress has been made in the recent years.

Botulinum Neurotoxin Assays in Human Neural Models

Question from the audience
Have your models been tested for the assay and function of botulinum neurotoxin?

Dr. Da Cruz’s answer  
We have not systematically optimized the model for botulinum neurotoxin assays. However, given the presence of functional synaptic machinery, the platform should in principle be suitable for probing synaptic transmission blockade, pending dedicated validation.

Spatial Transcriptomics, RNA Localization, and Axonal Vulnerability

Question from the audience
Please could you expand on how spatial transcriptomics data can be translated into constraints for theoretical models of axonal vulnerability.

Dr. Da Cruz’s answer  
Spatial transcriptomics allows mapping of gene expression gradients across somato-dendritic and axonal compartments. These data can inform model parameters such as local translation capacity, metabolic demand, transport efficiency, and stress responses—providing spatially resolved constraints for predicting where and why degeneration initiates.

Question from the audience
How can spatial transcriptomics be used to identify early subcellular RNA localization changes associated with synaptic dysfunction and neurodegeneration in Alzheimer’s disease?

Dr. Da Cruz’s answer
Spatial approaches can identify mislocalization of synaptic mRNAs (e.g., reduced dendritic or axonal targeting) before overt pathology. By integrating subcellular resolution data with disease progression, it becomes possible to detect early disruptions in RNA transport and local translation that precede synaptic failure.

Linking Molecular Changes to Neuronal Electrophysiology

Question from the audience
How can molecular changes (e.g. RNA localization) be linked to electrophysiological function in neurons?

Dr. Da Cruz’s answer
This can be achieved by correlating perturbations in RNA localization or translation with functional outputs such as synaptic strength, firing patterns, or network activity. Combining imaging/transcriptomics with MEA or patch-clamp recordings enables causal links between molecular deficits and functional impairment.

Selective Vulnerability and Disease Progression in Motor Neuron Disease

Question from the audience
Why do you think ocular motor neurons survive until the end in ALS and spared in SMA?

Dr. Da Cruz’s answer
These neurons likely benefit from a combination of intrinsic properties (e.g., calcium buffering, gene expression programs, proteostasis capacity) and extrinsic support (e.g., synaptic inputs, trophic factors). Their resistance highlights protective pathways that could be leveraged therapeutically. This is indeed a line of research ongoing in the lab to elucidate molecular hallmarks underlying resistance/vulnerability.

Question from the audience
Does the degeneration of upper motor neurons drive spinal cord neuron degeneration or vice versa?

Dr. Da Cruz’s answer  
While corticospinal (upper motor neuron) degeneration can drive downstream vulnerability, lower motor neuron and NMJ pathology occur early and importantly in all ALS forms. This is why it is critical to understand why NMJs are lost so early since targeting such early demise will have wide implications for all patients.