Ubiquitin signaling in neurodegenerative diseases: an autophagy and proteasome perspective

Abstract

Ubiquitin signaling is a sequence of events driving the fate of a protein based on the type of ubiquitin modifications attached. In the case of neurodegenerative diseases, ubiquitin signaling is mainly associated with degradation signals to process aberrant proteins, which form aggregates often fatal for the brain cells. This signaling is often perturbed by the aggregates themselves and leads to the accumulation of toxic aggregates and inclusion bodies that are deleterious due to a toxic gain of function. Decrease in quality control pathways is often seen with age and is a critical onset for the development of neurodegeneration. Many aggregates are now thought to propagate in a prion-like manner, where mutated proteins acting like seeds are transitioning from cell to cell, converting normal proteins to toxic aggregates. Modulation of ubiquitin signaling, by stimulating ubiquitin ligase activation, is a potential therapeutic strategy to treat patients with neurodegeneration diseases.

Fig. 1. Degradation of misfolded proteins by UPS and ALP.

A Newly synthesized proteins are folded by chaperones. Misfolded proteins that cannot be re-folded by chaperones can aggregate in ubiquitinated inclusions due to genetic and environmental factors. B Not-yet toxic aggregates can be targeted early by a functional UPS or ALP response, preventing neuron death and ND. On the other hand, due to factors like age or mutations in key genes, toxic aggregates develop, leading to deadly ND.

Fig. 2. Example of aggregate prone proteins.

A α-synuclein, involved in synapse function, can aggregate into LB, subsequently inhibiting UPS and ALP responses, progressing into PD. B Amyloid-β can degenerate into amyloid plaques as it inhibits the UPS response. C Tau can become phosphorylated and ubiquitinated, leading to neurofibrillary tangles and cross-talk with a-β, impairing ALP and UPS, leading to AD.

Fig. 3. Therapeutic strategies to mitigate aggregates: targeted protein degradation.

A Different strategies including modulating E3 ubiquitin ligases and DUBs, modulating the UPS and ALP using small molecules as well as PROTACs and AUTACs are currently explored to prevent toxic aggregate formation and development of NDs. B PROTAC is a bifunctional-hybrid compound that possess a ligand to the target protein, a ligand to an E3 ubiquitin ligase and a linker in between these two ligands. By spacially connecting an E3 ligase and the target protein, the E3 ligase will ubiquitinate the target protein and direct it to UPS degradation. PROTAC can then be recycled back for subsequent rounds of degradation. C AUTAC can come in two different flavors, the first one possessing one end consisting of a ligand to the target protein and the other end consisting of S-guanylation. The target protein will then be directed for selective autophagy degradation. S-guanylation is a standalone tag for ALP degradation. The second technology is based on small molecule screening that specifically recognize the polyQ stretch of mHTT and LC3, specifically targetting mHTT to the autophagosome.