ALS, FTD, and Alzheimer?s are complex diseases that each result from many diverse genetic etiologies. Although therapeutic strategies that target specific causal mutations (e.g. SOD1 ASOs) may prove effective against individual forms of ALS and FTD, these approaches cannot address the vast majority of cases that have unknown genetic etiology. Moreover, given the large number of different genes that likely contribute to ALS and FTD and the fact that each genetic form is relatively rare, this strategy may be difficult to implement for all cases. Thus, there is a pressing need for new therapeutic strategies that rescue multiple forms of ALS and FTD, particularly those with unknown genetic etiologies. To identify new therapeutic targets that rescue multiple forms of ALS, we performed unbiased chemical screens to search for targets that can rescue the degeneration of iPSC motor neurons from multiple C9ORF72 and sporadic ALS patients. Inhibitors of PIKFYVE kinase were among the most potent and broadly-efficacious compounds across patient lines. Surprisingly, the data show that PIKFYVE inhibition rescues neurodegeneration by blocking autophagosome- lysosome fusion, which induces secretory autophagy to clear misfolded proteins including C9ORF72 dipeptide repeat proteins and TDP-43 through exosomal secretion. The accumulation of misfolded proteins can induce neuron death and is a common feature of neurodegenerative diseases. Although studies have sought to stimulate known proteostasis pathways including the proteosome and autophagy, these pathways decline during aging and may be difficult to rescue effectively. Intriguingly, recent studies have shown that neurons use exosomal secretion as a third proteostasis pathway. However, it remains unknown if this pathway can be harnessed to treat ALS and related neurodegenerative diseases. The central hypothesis of the proposed study that secretory autophagy is one of the most potent ways to prevent neurodegeneration in ALS, FTD, and Alzheimer?s disease differs from mainstream thinking in the field. Evaluating this hypothesis is crucial because activating the proteasome and autophagy has had mixed results in neurodegeneration models. The proposed study will 1) confirm that secretory autophagy is the therapeutic mechanism of PIKFYVE inhibition, 2) determine the efficacy of secretory autophagy in ALS, FTD, and Alzheimer?s disease patient-derived neurons, and 3) validate the efficacy of PIKFYVE suppression with antisense oligonucleotides in vivo. This application seeks to shift current research by validating the induction of secretory autophagy as a highly effective therapeutic strategy for diverse forms of ALS, FTD, and Alzheimer?s disease. The proposed study will establish PIKFYVE suppression and secretory autophagy as critical therapeutic targets for ALS and related neurodegenerative diseases. More broadly, this therapeutic strategy may be effective for other diseases driven by aberrant protein accumulation.

Public Health Relevance

There is a pressing need for new therapeutic strategies that rescue multiple forms of ALS and FTD, particularly those with unknown genetic etiologies. The proposed study will validate a new therapeutic mechanism, the induction of secretory autophagy, that we found through high-throughput screening to be one of the most potent ways of rescuing the degeneration of neurons derived from patients with diverse forms of ALS. We anticipate that this study will establish PIKFYVE kinase suppression and the activation of secretory autophagy as critical therapeutic targets for ALS, FTD, and related neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS097850-05
Application #
10053096
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Gubitz, Amelie
Project Start
2017-07-01
Project End
2025-06-30
Budget Start
2020-07-15
Budget End
2021-06-30
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Southern California
Department
Physiology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Wilkinson, Brent; Evgrafov, Oleg V; Zheng, DongQing et al. (2018) Endogenous Cell Type-Specific Disrupted in Schizophrenia 1 Interactomes Reveal Protein Networks Associated With Neurodevelopmental Disorders. Biol Psychiatry :
Kramer, Nicholas J; Haney, Michael S; Morgens, David W et al. (2018) CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity. Nat Genet 50:603-612
Shi, Yingxiao; Lin, Shaoyu; Staats, Kim A et al. (2018) Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat Med 24:313-325
Ichida, Justin K; Staats, Kim A; Davis-Dusenbery, Brandi N et al. (2018) Comparative genomic analysis of embryonic, lineage-converted and stem cell-derived motor neurons. Development 145:
Patten, Shunmoogum A; Aggad, Dina; Martinez, Jose et al. (2017) Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis. JCI Insight 2:
Pepper, Jon-Paul; Wang, Tiffany V; Hennes, Valerie et al. (2017) Human Induced Pluripotent Stem Cell-Derived Motor Neuron Transplant for Neuromuscular Atrophy in a Mouse Model of Sciatic Nerve Injury. JAMA Facial Plast Surg 19:197-205