Human Amyotrophic Lateral Sclerosis iPSC-Derived Models - ALS Disease Models

Understanding ALS - Disease Mechanisms

ALS manifests in two primary forms: familial ALS (fALS), which affects approximately 10% of patients and has a genetic basis, and sporadic ALS, which comprises the majority of cases. Both forms share clinical characteristics and present significant challenges in diagnosis and treatment. 

The causes of this disease are not fully understood. The TAR DNA-binding protein 43, TDP-43, is, in most cases, mislocalized and aggregated. In familial forms with a C9orf72 mutation of GGGGCC copy variants, RAN-translation mistakes with the generation of toxic dipeptides induce TDP-43 defects. These complex mechanisms also affect the innate immune system. The C9orf72 caused cases and frontotemporal dementia (FTD). 

TDP-43 dysfunction causes STMN2 truncation, which is toxic.

ALS is affecting the neuromuscular gap junction. It is not clear if this is an early or late consequence of this disease. Non-neuronal glial cells also seemed to be involved in ALS. We have shown that diseased astrocytes have a strong toxic effect. Astrocytes ensure glutamate homeostasis in motor neurons. Hyperexcitation and glutamate excitotoxicity are some of the pathological mechanisms in ALS. Glutamate excitotoxicity is one convergent mechanism of all forms of ALS and is, therefore, a critical target for sporadic forms of ALS. We have demonstrated that C9orf72, SOD1, and TDP-43 cell lines develop over time hyperexcitation.

It is striking that ALS is often affecting people with a low body mass index and hypolipidemia. Lipide metabolism is dysregulated in the white matter of ALS patients, and the neurofilament light chain, NF-L, is most expressed in myelinated cells. NF-L is one of the most robust biomarkers in NF-L. It is worth mentioning that in ALS motor neurons, NF-L is located at the axion initial segment, where it causes hyperexcitation. Since energy metabolism is one of the main dysfunctions in ALS, we have integrated energy metabolism analysis in our biomarker portfolio.

Environmental reasons are supposed to have an influence on ALS pathogenesis. The protein β-Methylamino-L-alanine, BMAA, is one candidate to provoke ALS.

The Need for Advanced ALS Models

Developing effective therapies for ALS is exceptionally challenging, with a high attrition rate in clinical trials. To address this, advanced and validated ALS models are crucial for accurately studying ALS pathogenesis and screening potential treatments.

Our Approach: iPSC-derived motor neuron models of ALS

At NeuroProof, we employ a rigorous assay validation strategy encompassing constructed, face, and predictive validation methods to ensure the reliability and relevance of our models.

We offer phenotypic screening assays to target amyotrophic lateral sclerosis.

Our primary focus is on the use of induced pluripotent stem cells (iPSC)-derived spinal motor neurons from human origin. They offer a versatile platform for modeling ALS pathology and conducting phenotypic screening. These cells are available in co-culture models with astrocytes and microglia.

Key Mutations and Mechanisms:

Our iPSC-derived motor neurons include mutations associated with familial ALS, such as C9orf72, SOD1, and TDP43, which cover a spectrum of pathological mechanisms implicated in ALS progression.

These mutations contribute to various aspects of ALS pathology, including protein misfolding, oxidative stress, mitochondrial dysfunction, energy metabolism dysfunction, and excitotoxicity, providing valuable insights into disease mechanisms.

Hyperexcitation Assays

Utilizing electrophysiological MEA recordings, our hyperexcitation assays mimic pathological neuronal activity observed in ALS, offering a valuable tool for disease modeling and drug screening.

We demonstrate disturbed excitatory-inhibitory balance in ALS mutant cell lines, highlighting their relevance for studying disease mechanisms and evaluating therapeutic interventions.

Comprehensive Screening Services

Our assays encompass a range of readouts of different biomarkers, including molecular markers such as TDP-43 accumulation, cell viability assays, and imaging techniques, providing a holistic approach to ALS research.

Customers can customize their screening protocols, including standalone MEA readouts or combinations with other assays tailored to their specific research needs.

Continuous Innovation

NeuroProof is committed to expanding our assay portfolio to address emerging challenges in ALS research, including the development of new cell lines and co-culture systems with astrocytes and microglia.

From sourcing diseased cell lines to compound screening campaigns, we offer integrated project solutions to accelerate ALS drug discovery efforts.

Contact Us

For further information on our ALS iPSC model and assay services or to discuss collaboration opportunities, please contact us.