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The Role of Energy Metabolism in ALS Progression

Energy metabolism in diseased ALS cells is severely disrupted, with mitochondrial dysfunction, altered glucose and lipid metabolism, and increased oxidative stress at the core of the disease. These metabolic dysfunctions not only result from neurodegeneration but also actively contribute to disease progression. By targeting these pathways, researchers can identify promising therapeutic strategies and novel drug targets for ALS.

Innovative Technology for ALS Research

NeuroProof has been at the forefront of ALS research, developing disease models with complex iPSC-derived cell cultures that support the validation of drug targets and compound's therapeutic potential by improving predictivity in drug screening campaigns and providing customer-specific assay development. With the integration of Doppelganger's cutting-edge QSM™ platform, NeuroProof now quantifies metabolite turnover rates across 22 principal metabolic pathways, including critical aspects of cellular bioenergetics like glycolysis and oxidative phosphorylation (OXPHOS).

The QSM™ platform, validated for use with single cells and various tissue types, enables precise analysis of energy metabolism due to hyperexcitation in ALS cells. This is the first service combining NeuroProof's multielectrode array (MEA) technology with Doppelganger's metabolic phenotyping capabilities.

Comprehensive ALS Screening Services

The new ALS screening service thoroughly evaluates metabolic dysfunctions in ALS disease models. Services include:

- Validation of ALS disease models

- Counter-screening assays

- Predictivity improvement in drug screening campaigns

- Single-assay prescreening for potential therapeutic compounds

This unique combination of electrophysiological and metabolic analyses delivers a comprehensive understanding of how compounds impact key metabolic pathways, such as ATP production, pyruvate, branched-chain amino acids (BCAAs), and fatty acid metabolism. The data generated through these studies offer valuable insights for developing therapeutic interventions, including dietary strategies tailored to ALS patients.

Contact Us for More Information

For further details about our innovative ALS screening service and how it can support your research, please contact us. Discover how functional neuro-metabolic can unlock new potential in ALS treatment development.

About NeuroProof Systems GmbH

NeuroProof is a leader in developing biomarker assays for neurodegenerative diseases, particularly ALS. With cutting-edge electrophysiological techniques and metabolic screening technologies, NeuroProof is dedicated to improving the predictivity and efficacy of therapeutic development.

About Doppelganger

Doppelganger specializes in advanced metabolic phenotyping technologies. Its QSM™ platform, used across various disease areas, enables precise metabolic turnover rate analysis and provides critical insights into cellular energy dynamics.

NeuroProof Systems GmbH and BrainXell Inc., Madison, Wisconsin, collaborate to develop innovative in vitro assays on the basis of:

• BrainXell's human iPSC-derived spinal motor neurons, astrocytes, and microglia from patients with C9orf72, SOD1, TDP-43, and FUS mutations.
• NeuroProof has optimized differentiation and cultivation of these cells on microelectrode arrays and microscopic plates.
• Long-term cultivation shows a reproducible and substantial readout for electrophysiology, microscopy, and molecular biomarkers.
• NeuroProof has performed successful projects with more than 30 customers.

In Boston, we present:

• How long-term cultivation gains hyperexcitation behavior in diseased cultures. Hyperexcitation seems to be the strongest functional phenotypic readout in ALS.
• Examples of compounds that demonstrate the predictive capacity of our assays.
• Examples of our new microscopy assays for TDP-43 mislocalization and as neurite outgrowth is an additional biomarker to assess a compound's therapeutic potential.

C9orf72 motor neurons exhibit TDP-43 condensates in somas and axons.

ALS pathology is only partially understood. TDP-43 proteins play an essential role in the mechanisms of this severe disease. Some evidence indicates that TDP-43 is an early marker of this disease starting from the neuromuscular junction.
 
NeuroProof investigated several markers of ALS in an automated imaging approach with the CQ1 system from Yokogawa in collaboration with Cenibra GmbH. In this study, TDP-43 was present in axons in C9orf72 spinal motor neurons, which is in concordance with other publications.
  
Phenotypic screening of human iPSC-derived motor neurons from patients with familial history is an excellent opportunity for screening new therapies for this severe disease.
 
NeuroProof has tested diseased ALS motor neurons with and without co-cultures of astrocytes in several screening assays besides its electrophysiological screening on its microelectrode array recording platform.

In the picture, we have stained C9orf72 human iPSC-derived motor neurons after 14 days in vitro with a TDP-43 antibody (green, nuclei with DAPI in blue, and cytoskeleton with ß-III-Tubulin in red).

Nov 12 at 1:00 PM
Functional Phenotypic Screening of Small Molecules in a human patient-derived cell model for Fragile X Syndrome
 
We developed a functional phenotypic assay with a diseased human cell line from a fragile X patient.
 
Cortical neurons derived from this disease cell line showed clear functional different activity patterns compared to a wild-type cell line.
 
We screened more than 200 compounds in this model with an MEA screen.
 
We identified the phosphodiesterase 10A inhibitor balipodect (TAK-063) as a potential new treatment for FXS.
 
We compared the potential therapeutic effects of balipodect, mavoglurant, arbaclofen, and lovastatin with this model.
 
Nov 16 at 8.00 AM
Functional Phenotypic Screening Models for Amyotrophic Lateral Sclerosis with human iPSC-derived spinal motor neurons

Compared to wild-type cell lines, the hyper excitation of diseased ALS cell lines with a C9orf72 and a SOD1 mutation is shown.

The effect of astrocytes on neuronal activity was investigated.
 
The effects of riluzole and spermidine in these models are shown.

Nov 16 at 8:00 AM
Validation of Models for Amyotrophic Lateral Sclerosis with human iPSC Motor-derived Neurons

Mislocalization of TDP-43 proteins in axons and dendrites is a hallmark of ALS. TDP-43 mislocalizations exist in iPSC-derived spinal motor neurons with C9orf72 mutations but not in wild-type motor neurons.
 
In the picture, we have stained C9orf72 human iPSC-derived motor neurons after 14 days in vitro with a TDP-43 antibody (green, nuclei with DAPI in blue, and cytoskeleton with ß-III-Tubulin in red).

C9orf72 mutant cells show increased levels of Poly(GR) dipeptides as a second hallmark.

Visit our presenter and discuss our new developments.