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.