Uniting homeostatic plasticity and exosome biology: A revision of the conceptual framework for drug discovery in neurodegenerative diseases?

Neurodegenerative diseases (NDDs) are in need of new drug discovery approaches. Our previous systematic analyses of Huntington's Disease (HD) literature for protein-protein interactors (PPIs) and modifiers of mutant Huntingtin-driven phenotypes revealed enrichment for PPIs of genes required for homeostatic synaptic plasticity (HSP) and exosome (EV) function and exosomal proteins, which in turn highly overlapped each other and with PPIs of genes associated with other NDDs. We proposed that HSP and EVs are linked to each other and are also involved in NDD pathophysiology. Recent studies showed that HSP is indeed altered in HD and AD, and that presynaptic homeostatic plasticity in motoneurons compensates for ALS pathology. Eliminating it causes earlier degeneration and death. If this holds true in other NDDs, drug discovery in animal models should then include elucidation of homeostatic compensation that either masks phenotypes of physiologically expressed mutant genes or are overridden by their overexpression. In this new conceptual framework, enhancing such underlying homeostatic compensation forms the basis for novel therapeutic strategies to slow progression of NDDs. Moreover, if EVs are linked to HSP, then their ability to penetrate the brain, target cell types, deliver miRNA and other molecules can be leveraged to develop attractive drug modalities. Testing this new framework is posed as four questions on model development and mechanistic studies progressing from higher throughput platforms to mouse models. Similar approaches may apply to other CNS disorders including schizophrenia, autism, Rett and Fragile X syndromes due to potential links of their susceptibility genes to HSP and EVs.