Neurons undergo pathogenic metabolic reprogramming in models of familial ALS

Riechers, Sean-Patrick; Mojsilovic-Petrovic, Jelena; Belton, Tayler B.; Chakrabarty, Ram Prosad; Garjani, Mehraveh; Medvedeva, V. K.; Dalton, Casey; Wong, Yvette C.; Chandel, Navdeep S.; Dienel, Gerald A.; Kalb, Robert G.

doi:10.1016/j.molmet.2022.101468

Cited by 10 publications

(8 citation statements)

References 127 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One further area of interest would be to characterize in much more detail changes in the efficiency of glycolytic and OXPHOS pathways and their interaction in MN-carrying ALS mutations. An increase in FUS-ALS MNs' survival upon stimulation of glycolysis as well as a clear shift in metabolic rates in all cell cultures after their prolonged cultivation suggests that some compensatory upregulation of glycolytic pathways could be beneficial to ALS MNs, as was reported in fALS models for mutations in SOD1 and TDP43 genes [97].…”

Section: Discussionmentioning

confidence: 64%

Live Cell Imaging of ATP Levels Reveals Metabolic Compartmentalization within Motoneurons and Early Metabolic Changes in FUS ALS Motoneurons

Zimyanin

Pielka

Glaß

et al. 2023

Cells

View full text Add to dashboard Cite

Motoneurons are one of the most energy-demanding cell types and a primary target in Amyotrophic lateral sclerosis (ALS), a debilitating and lethal neurodegenerative disorder without currently available effective treatments. Disruption of mitochondrial ultrastructure, transport, and metabolism is a commonly reported phenotype in ALS models and can critically affect survival and the proper function of motor neurons. However, how changes in metabolic rates contribute to ALS progression is not fully understood yet. Here, we utilize hiPCS-derived motoneuron cultures and live imaging quantitative techniques to evaluate metabolic rates in fused in sarcoma (FUS)-ALS model cells. We show that differentiation and maturation of motoneurons are accompanied by an overall upregulation of mitochondrial components and a significant increase in metabolic rates that correspond to their high energy-demanding state. Detailed compartment-specific live measurements using a fluorescent ATP sensor and FLIM imaging show significantly lower levels of ATP in the somas of cells carrying FUS-ALS mutations. These changes lead to the increased vulnerability of diseased motoneurons to further metabolic challenges with mitochondrial inhibitors and could be due to the disruption of mitochondrial inner membrane integrity and an increase in its proton leakage. Furthermore, our measurements demonstrate heterogeneity between axonal and somatic compartments, with lower relative levels of ATP in axons. Our observations strongly support the hypothesis that mutated FUS impacts the metabolic states of motoneurons and makes them more susceptible to further neurodegenerative mechanisms.

show abstract

Section: Discussionmentioning

confidence: 64%

Live Cell Imaging of ATP Levels Reveals Metabolic Compartmentalization within Motoneurons and Early Metabolic Changes in FUS ALS Motoneurons

Zimyanin

Pielka

Glaß

et al. 2023

Cells

View full text Add to dashboard Cite

show abstract

“…One further area of interest would be to characterize in much more detail changes in efficiency of glycolytic and OXPHOS pathways and their interaction in MN carrying ALS mutations. Increase in FUS-ALS MNs survival upon stimulation of glycolysis as well as clear shift in metabolic rates in all cell cultures after their prolonged cultivation suggests that some compensatory upregulation of glycolytic pathways could be beneficial to ALS MNs as was reported for in fALS models for SOD1 and TDP43 [99].…”

Section: Discussionmentioning

confidence: 91%

Live cell imaging of ATP levels reveals metabolic compartmentalization within motoneurons and early metabolic changes inFUSALS motoneurons

Zimyanin

Pielka

Glaß

et al. 2023

Preprint

View full text Add to dashboard Cite

Motoneurons are one of the highest energy demanding cell types and a primary target in Amyo-trophic lateral sclerosis (ALS), a debilitating and lethal neurodegenerative disorder without current-ly available effective treatments. Disruption of mitochondrial ultra-structure, transport and metabo-lism is a commonly reported phenotype in ALS models and can critically affect survival and proper function of motor neurons. However, how changes in metabolic rates contribute to ALS progression are not fully understood yet. Here we utilize hiPCS derived motoneuron cultures and live imaging quantitative techniques to evaluate metabolic rates in Fused in Sarcoma (FUS)-ALS model cells. We show that differentiation and maturation of motoneurons is accompanied by an overall upregulation of mitochondrial components and significant increase in metabolic rates that corresponds to their high energy-demanding state. Detailed compartment-specific live measurements using a fluorescent ATP sensor and FLIM imaging show significantly lower levels of ATP in the somas of cells carrying FUS-ALS mutations. These changes lead to the increased vulnerability of disease motoneurons to further metabolic challenges with mitochondrial inhibitors and could be due to the disruption of mi-tochondrial inner membrane integrity and an increase in its proton leakage. Furthermore, our measurements demonstrate heterogeneity between axonal and somatic compartments with lower relative levels of ATP in axons. Our observations strongly support the hypothesis that mutated FUS impacts metabolic states of motoneurons and makes them more susceptible to further neurodegener-ative mechanisms.

show abstract

“…This process allows us to have a more sustainable source of research material for studying neurological diseases. Moreover, several studies have been conducted on the in vitro reprogramming of neurons to establish disease models for various neurological disorders, such as ALS [ 181 ]. In animal models, cell transplantation therapy has been shown to effectively restore damaged neurological function [ 207 ].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, neuritogenesis can be enhanced by increasing the mitochondrial membrane potential, polarizing the mitochondria, and decreasing the reliance on glycolysis [ 180 ]. Because ATP generation is required for synaptic activity, neuronal activity strongly depends on normal functioning of neuronal mitochondria and energy metabolism [ 181 , 182 ]. As a result, one of the most visible aspects of the transdifferentiation process is the abrupt change in metabolism [ 33 ].…”

Section: Molecular Mechanisms Of Somatic Cell Transdifferentiation In...mentioning

confidence: 99%

Somatic Cell Reprogramming for Nervous System Diseases: Techniques, Mechanisms, Potential Applications, and Challenges

et al. 2023

View full text Add to dashboard Cite

Nervous system diseases present significant challenges to the neuroscience community due to ethical and practical constraints that limit access to appropriate research materials. Somatic cell reprogramming has been proposed as a novel way to obtain neurons. Various emerging techniques have been used to reprogram mature and differentiated cells into neurons. This review provides an overview of somatic cell reprogramming for neurological research and therapy, focusing on neural reprogramming and generating different neural cell types. We examine the mechanisms involved in reprogramming and the challenges that arise. We herein summarize cell reprogramming strategies to generate neurons, including transcription factors, small molecules, and microRNAs, with a focus on different types of cells.. While reprogramming somatic cells into neurons holds the potential for understanding neurological diseases and developing therapeutic applications, its limitations and risks must be carefully considered. Here, we highlight the potential benefits of somatic cell reprogramming for neurological disease research and therapy. This review contributes to the field by providing a comprehensive overview of the various techniques used to generate neurons by cellular reprogramming and discussing their potential applications.

show abstract

Neurons undergo pathogenic metabolic reprogramming in models of familial ALS

Cited by 10 publications

References 127 publications

Live Cell Imaging of ATP Levels Reveals Metabolic Compartmentalization within Motoneurons and Early Metabolic Changes in FUS ALS Motoneurons

Live Cell Imaging of ATP Levels Reveals Metabolic Compartmentalization within Motoneurons and Early Metabolic Changes in FUS ALS Motoneurons

Live cell imaging of ATP levels reveals metabolic compartmentalization within motoneurons and early metabolic changes inFUSALS motoneurons

Somatic Cell Reprogramming for Nervous System Diseases: Techniques, Mechanisms, Potential Applications, and Challenges

Contact Info

Product

Resources

About