Saturday, May 17, 2025
5/17/2025
Restoring neuronal degradative capacity as a therapeutic strategy to treat Prion Disease - Prionopathies are rare human neurodegenerative diseases (ND) characterized by spongiform change, gliosis, and the deposition of misfolded prion protein (PrP) aggregates in and outside neurons across the brain. While cellular mechanisms remain largely undefined, evidence points toward a particular vulnerability of axons to the formation of misfolded PrP aggregates, and their accumulation inside lysosome-like compartments that contain incompletely digested material suggestive of defective lysosomal degradative pathways. These enlarged organelles are also an early pathological feature in brains of patients with Alzheimer’s Disease and Alzheimer’s Disease related dementias. Indeed, abnormal autophagic activity has been observed in brains of Alzheimer’s Disease, Alzheimer’s Disease Related Dementia, and prion disease patients, and activation of autophagy restores impaired lysosomal flux and reduces protein aggregates in cellular and ND animal models. Compelling evidence shows that PrP aggregates in axons impair neuronal function by driving the accumulation of organelles/vesicles and poisoning axonal transport. Thus, pharmacological targeting of toxic axonal aggregates via activation of autophagy could be a key strategy for preventing or ameliorating neuronal dysfunction in the proteinopathies. This application builds on our previous findings that identified an endolysosomal pathway unique to axons that promotes the initial stages of formation of misfolded mutant PrP aggregates inside enlarged endolysosome structures called ’endoggresomes’, that hyper-acidify and thus fail to degrade mutant PrP from axons, indicating impaired lysosomal degradation. This pathway is called axonal rapid endosomal sorting and transport-dependent aggregation (ARESTA), and genetic reduction of ARESTA genes efficiently inhibits mutant PrP endoggresome formation in axons, and restores neuronal function. In this application, we outline a therapeutic strategy to treat prionopathies. It is based on a small molecule A5, that we identified in a screen for lysosomal flux activators, and that activates macroautophagy via nuclear translocation of the transcription factor EB (TFEB), which controls transcription of lysosome and autophagosome biogenesis. A5 clears neurotoxic mutant PrP endoggresomes in axons of primary neurons, normalizing completely axonal transport impairments in cultured neurons expressing mutant PrP. Notably, A5 treatment reduces brain pathology in a mouse model of inherited prion disease. A5 degrades PrP aggregates at concentrations in the lower nanomolar range, shows no overt signs of toxicity in mice, and has brain penetrance. The proposed aims will test the efficacy of A5 in neuronal and mouse models of familial and infectious prion disease. We will also identify the mechanisms of action (MoA) of A5 by identifying interaction partners and characterizing the role of TFEB. Our findings reveal a therapeutic strategy to treat prionopathies by pharmacological activation of macroautophagy. As lysosomal clearance is commonly impaired in Alzheimer’s Disease and in Alzheimer’s Disease related dementias, our findings are also expected to be relevant to treating these disorders.
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