In collaboration with the ALS Association, we are pleased to announce the recent funding of four new grants designed to elucidate the biological linkages between key drivers of active axonal degeneration and ALS. ALS Finding a Cure® and the ALS Association are pleased to further scientific advances in this important area of research, which are sure to lead to future therapeutic insights. The four projects funded through the Arrest ALS collaboration include:
Bloom/DiAntonio submission (Washington University in St. Louis):
Pathological aggregation of the protein TDP-43 within motor neurons is seen in the majority of ALS cases (sporadic and familial). TDP43 dysfunction prevents axons from regenerating and can lead to axonal degeneration. This project would investigate two potential explanations for why TDP43 dysfunction promotes axonal degeneration in ALS: (1) loss of a key axon-survival promoting factor, and (2) activation of an axon-destruction pathway. The collaboration proposes to extensively characterize a unique set of “humanized” ALS mouse models and then to test various approaches to rescue disease in these mouse models (i.e. a gene therapy, an anti-inflammatory approach, and a transgenic approach).
Coleman/Sreedharan submission (Cambridge University/Kings College London):
The investigators recently identifed variations of a gene known to be responsible for the axon destruction pathway in ALS patients. These gene changes appear to increase the likelihood that neurons will trigger the axon destruction pathway. This project would convert stem cells from ALS patients with these gene variations into neurons and use them to identify other genes and cell changes interacting with and resulting from the presence of these gene variations.
Freeman lab submission (Vollum Institute, Oregon Health Sciences):
This investigator originally used fruit fly models to identify the main driver of the axon destruction pathway, following cutting of axons, as well as several genes that could influence this pathway. The proposed project would use a different approach to trigger the axon destruction pathway in fly models and then look for additional genes that can modulate this pathway. Following this, the investigators would use a similar approach to triggering axon destruction to create a zebrafish model in which to test the modulators identified in the fly.
Lagier-Tourenne/Ward submission (Harvard/NIH):
The investigators recently identified a direct link between TDP-43 and an axonal regeneration factor, whereby dysregulation of TDP43 leads to the disappearance of this axonal regeneration factor in animal models and to significant loss in ALS patients. This project would identify genes and drug compounds that influence levels of the axonal regeneration factor, using a combination of cell-based screening strategies, in an effort to increase and potentially restore levels of the axonal regeneration factor.a