TDP-43 Proteins in Axons of C9orf72 Mutations are Validating iPSC-Derived Motor Neurons as a Model of Amyotrophic Lateral Sclerosis

16 June, 2022

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).

Visit us at SfN meeting Nov. 12-16, 2022 in San Diego

15 June, 2022

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.

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New Assay for Gaucher’s and Parkinson’s Disease With GBA mutations

09 December, 2021

New GBA mutation-based disease models open opportunities for more physiologically adequate screening methods.

GBA mutations with relevance in Gaucher's and Parkinson's disease.

NeuroProof expands its human iPSC-derived functional disease models with GBA mutation cell lines. 

GBA mutations of the glucocerebrosidase enzyme (GCase) are responsible for Gaucher's disease but are also relevant in Parkinson’s disease. More than 10% of patients with Parkinson’s disease carry a GBA mutation.
A multitude of GBA mutations is known with different clinical symptoms and different involvement of Parkinsonism. Heterozygous and homozygous mutations cause different symptoms and severity of diseases.

The molecular pathways of these lysosomal storage disorders and their relation to Parkinson’s disease are not fully understood. GBA mutations decrease the activity of GCase, causing an increase in alpha-synuclein. A phenotypic screen promises an excellent approach for drug testing.

Patients with Gaucher’s disease also experience neurological symptoms that can not be treated by enzyme replacement or substrate reduction therapies because of their missing capacity to cross the blood-brain barrier.
For the discovery of new Gaucher’s and Parkinson’s treatments, testing compounds in different GBA mutated diseases will increase predictivity significantly.

Neuroproof can now deliver screening services with human iPSC-derived glutamatergic neuron disease models, starting with a GBA null/null mutation and others following soon. The cells were grown on MEA-plates and showed a hyperexcited activity pattern and a clear difference between the mutated and the diseased cell lines. On customer request, NeuroProof combines its MEA screening with molecular readouts for phosphorylated alpha-synuclein expression, for example.

The new GBA mutation disease model expands NeuroProof iPSC-derived human patient-derived disease models. 

To learn more about these new assays, contact us to request more information.

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