Many of us would like to believe that “the Ice Bucket Challenge was the beginning of ending ALS” as phrased by Pat Quinn, one of the Ice Bucket Challenge founders (Sohn, 2017). In 2014, the Ice Bucket Challenge raised global awareness and millions of dollars for research on the neurodegenerative disease, amyotrophic lateral sclerosis (ALS). However, eight year later, few people have followed up with the impacts of the challenge, and the research that has emerged from the funds raised.
ALS is a fatal neuromuscular disease characterized by the degeneration of motor neurons (Grad, et al., 2017), which affects 1.8 in every 100 000 North Americans (Chiò, et al., 2013). In classical ALS, muscle weakness begins in the face, arm, or leg, and advances to other regions (Grad, et al., 2017). Due to the wide range of clinical phenotypes, ALS is extremely difficult to categorize and it is highly debated whether these phenotypes should be categorized under one broad disease or as several distinct diseases. The molecular mechanisms that characterize ALS overlap with other neurodegenerative diseases, including frontotemporal dementia (Ling, Polymenidou and Cleveland, 2013).
TAR-DNA binding protein 43 (TDP-43) is a protein involved in ALS pathology (Lee, Lee and Trojanowski, 2012). Numerous post-translational modifications to this RNA-binding protein (Figure 1a) can cause the formation of aggregates which contribute to the deterioration of neurons (Ling, Polymenidou and Cleveland, 2013; Prasad et al., 2019). One modification, ubiquitination, causes TDP-43 to become a component of ubiquitinated inclusions (UBIs), which are clusters of misfolded proteins that form specifically in patients manifesting frontotemporal dementia (Forman, Trojanowski and Lee, 2004). Ubiquitination is a method in which cells are targeted for degradation via the proteasome, a large cytosolic protease containing degrading enzymes (Nandi et al., 2006). TDP-43 loses its normal nuclear localization and is mislocated to the cytoplasm in neurons with UBIs (Figure 1b; Neumann, et al., 2006).
Funds raised by the Ice Bucket Challenge enabled research which further elucidated the mechanism of pathological TDP-43 in ALS. The Wong lab performed RNA sequencing analysis to find that TDP-43 represses cryptic exon splicing, which is seen in ALS (Ling, et al., 2015). This furthered the understanding of TDP-43 pathology and provided a basis for further research.
In addition to TDP-43 research, the Ice Bucket Challenge funds continue to impact the development of ALS treatments. On September 29, 2022, the ALS Association announced that a new drug to treat ALS, funded by Ice Bucket Challenge proceeds, was approved by the FDA (Frederick, 2022). The drug, AMX0035, mitigates neuronal death in ALS cases by treating dysfunction of the endoplasmic reticulum and mitochondria, and showed significant functional and survival benefits for adults with ALS in clinical trials (Paganoni, et al., 2021). The emergence and approval of this drug is a major leap in the progress of treating ALS, which has long been believed to be uncurable; rehabilitation and gene therapy were previously the only options for patients (Majmudar, Wu and Paganoni, 2014; Amado and Davidson, 2021)
The Ice Bucket Challenge provided the opportunity for many researchers to advance the studies of ALS and its biomarkers. ALS remains a subject of intensive research sparked by the funding and awareness from the Ice Bucket Challenge, although it continues to challenge patients, researchers and caregivers.
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