This project responds to NIH Directors TRA RFA-RM-20-013 and will test the hypothesis that homeostatic
restoration of small GTPase signaling to modify Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS)
pathogenesis is a game-changing therapeutic approach compared to unidirectional targeting. If proven, this new
and innovative paradigm will have far-reaching and transformative impact for targeting other chronic diseases
and disorders such as autism spectrum disorder, schizophrenia, and drug addiction.
The predominant and conventional therapeutic strategies in treating human diseases are unidirectionally
inhibiting or stimulating affected biological processes. However, in many chronic diseases such as AD and ALS,
complete inhibition or activation of the affected signaling events may themselves promote diseases. Disease
progression can also be spatiotemporal, with initial activation followed by inhibition or vice versa, as well as
activation versus inhibition at different brain regions. Thus, simple unidirectional targeting may itself be a major
reason that no drugs have successfully prevented, reversed or even modified the disease course for such
neurodegenerative disorders. To overcome this formidable challenge, new therapeutic paradigms must be
investigated. One approach is to restore homeostatic balance instead of completely inhibiting or activating the
affected signaling pathways. This approach is largely untested for AD and ALS but is broadly significant because
many other complex diseases also exhibit homeostatic imbalance and spatiotemporal dysregulation of signaling
pathways, making the use of inhibitors or activators ineffective if used inappropriately.
This TRA project proposes to restore the homeostatic balance of Rho and Rab family small GTPase
signaling, which is spatiotemporally dysregulated in AD and ALS. The classical Rho GTPases include RhoA,
Rac1, and Cdc42, in which RhoA often acts in opposition to Rac1 and Cdc42 to control protein processing and
trafficking as well as synaptic remodeling. Rab GTPases additionally control ER stress and protein aggregation.
Our project will apply innovative dual function small molecules to investigate this antagonism for restoring
their homeostatic balance. We will determine the effects of their modulation on AD and ALS hallmark proteins
and pathogenesis in mouse models. If successful, this project will deliver novel first-in-class drug leads, and the
new therapeutic paradigm will transform the entire AD and ALS drug development landscape and beyond.
In summary, our proposal provides a strong rationale for the transformative impact of establishing
homeostatic targeting at defective signaling processes in AD and ALS. With a multi-institution and multi-
disciplinary approach, this project will lead to novel and significant insights into whether targeting homeostatic
balances of defective signaling can modify AD and ALS disease course, providing a pioneering example of
applying the same approach for future targeting of other chronic and slow progression diseases.