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Updated: Aug 11, 2025
Real-Time Fluorescent Measurement of Synaptic Functions in Models of Amyotrophic Lateral Sclerosis
Published on: July 16, 2021
SYF2 suppression mitigates neurodegeneration in models of diverse forms of ALS
Gabriel R Linares1, Yichen Li1, Wen-Hsuan Chang2
1Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Abstract:
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by many diverse genetic etiologies. Although therapeutics that specifically target causal mutations may rescue individual types of ALS, such approaches cannot treat most patients since they have unknown genetic etiology. Thus, there is a critical need for therapeutic strategies that rescue multiple forms of ALS. Here, we combine phenotypic chemical screening on a diverse cohort of ALS patient-derived neurons with bioinformatic analysis of large chemical and genetic perturbational datasets to identify broadly effective genetic targets for ALS. We show that suppressing the gene-encoding, spliceosome-associated factor SYF2 alleviates TDP-43 aggregation and mislocalization, improves TDP-43 activity, and rescues C9ORF72 and causes sporadic ALS neuron survival. Moreover, Syf2 suppression ameliorates neurodegeneration, neuromuscular junction loss, and motor dysfunction in TDP-43 mice. Thus, suppression of spliceosome-associated factors such as SYF2 may be a broadly effective therapeutic approach for ALS.
Insights
Suppressing SYF2, a spliceosome factor, shows promise for treating multiple forms of Amyotrophic Lateral Sclerosis (ALS). This approach alleviates key disease pathology and improves motor function in preclinical models, offering a potential broad therapeutic strategy for ALS.
Area of Science:
- Neuroscience
- Genetics
- Drug Discovery
Background:
- Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with diverse genetic causes.
- Current treatments often target specific mutations, leaving many ALS patients without effective options due to unknown genetic etiologies.
Purpose of the Study:
- To identify broadly effective genetic targets for treating multiple forms of ALS.
- To discover therapeutic strategies that address the underlying pathology common to various ALS subtypes.
Main Methods:
- Combined phenotypic chemical screening of ALS patient-derived neurons.
- Bioinformatic analysis of large chemical and genetic perturbational datasets.
- Investigated the effects of suppressing SYF2 in cellular and mouse models of ALS.
Main Results:
- Suppression of SYF2 alleviates TDP-43 aggregation and mislocalization, crucial in ALS pathogenesis.
- SYF2 suppression rescues neuron survival in models of C9ORF72-linked and sporadic ALS.
- Syf2 suppression ameliorates neurodegeneration, neuromuscular junction loss, and motor dysfunction in TDP-43 mouse models.
Conclusions:
- Suppression of spliceosome-associated factors, exemplified by SYF2, represents a broadly effective therapeutic strategy for ALS.
- Targeting SYF2 offers a promising avenue for developing treatments applicable to a wider range of ALS patients.
