Molecules capable to induce neuroprotection via lysophagy activation

Accumulation of misfolded species prone to form toxic aggregates is a common hallmark of several neurodegenerative diseases (NDs), including polyglutamine (polyQ) diseases. Autophagy is the main protein degradative pathway involved in the clearance of protein aggregates and damaged organelles. Defects in autophagy are often observed in NDs, and may directly affect the accumulation of misfolded species. The pharmacological autophagy activation favors the clearance of misfolded proteins, and represents a possible therapeutic approach for NDs. Trehalose has been shown to be neuroprotective role in models of NDs, it exerts its functions activating autophagy, and removing the misfolded proteins accumulated into the cells. It has been already demonstrated that trehalose promotes autophagy via TFEB activation, but the exact mechanisms of autophagic activation was elusive. We found that trehalose induces a transient lysosomal enlargement and membrane permeabilization. This event activates TFEB through the calcium-dependent phosphatase calcineurin. Trehalose induces the upregulation of several autophagic and lysosomal genes, and TFEB downregulation prevents trehalose effects. Moreover, TFEB silencing counteracted trehalose pro-degradative activity. These results indicate that trehalose induces autophagy and lysosomal biogenesis through TFEB leading to the removal of damaged lysosome, a process called lysophagy, and restoring lysosomal homeostasis. TFEB activation is also associated with the clearance of mutant proteins from neurons. Unfortunately, in the human gut, trehalose is quickly degraded by the enzyme trehalase. We tested lactulose and melibiose, two trehalase-resistant analogues, and we observed that these compounds showed effects comparable to trehalose. Similarly, lactulose and melibiose induce lysophagy via TFEB. Emergent evidence suggests that lysosomal damage and defects in lysophagy are implicated in NDs. Our preliminary data suggest that polyQ proteins might induce lysosomal damage, possibly the failure of neurons to respond to this damage may affect lysosomal homeostasis, and contribute to neurodegeneration.