Impaired proteostasis in rare neurological diseases

Abstract

Rare diseases are classified as such when their prevalence is 1:2,000 or lower, but even if each of them is so infrequent, altogether more than 300 million people in the world suffer one of the ~7,000 diseases considered as rare. Over 1,200 of these disorders are known to affect the brain or other parts of our nervous system, and their symptoms can affect cognition, motor function and/or social interaction of the patients; we refer collectively to them as rare neurological disorders or RNDs. We have focused this review on RNDs known to have compromised protein homeostasis pathways. Proteostasis can be regulated and/or altered by a chain of cellular mechanisms, from protein synthesis and folding, to aggregation and degradation. Here we provide a compilation of 170 proteostasis-related RNDs, deepening on some representative diseases, including as well a clinical view of how those diseases are diagnosed and dealt with. Additionally, we review existing methodologies for diagnosis and treatment, discussing the potential of specific deubiquitinating enzyme inhibition as a future therapeutic avenue for RNDs.

How to Inactivate Human Ubiquitin E3 Ligases by Mutation

“…Mutations on E3 ligases have been associated with a number of diseases, including neurological disorders (George et al, 2018;Osinalde et al, 2019). Thus, understanding their mechanism of action, as well as identifying which substrates are regulated by each E3 at different developmental stages and cell types, will provide invaluable knowledge that might contribute to develop therapeutic strategies to treat these diseases.…”

Non‐syndromic X linked intellectual disability: Current knowledge in light of the recent advances in molecular and functional studies

“…Ubiquitination is a post‐translational modification that involves the addition of a small polypeptide called ubiquitin to target proteins. Neuronal maintenance of protein homeostasis is important for synaptic plasticity and requires a precise control of processes like protein synthesis, folding and degradation mainly by the ubiquitin proteasome system or autophagy . The ubiquitin proteasome system targets ubiquitinated proteins for proteasomal degradation and it is also involved in signal transduction.…”

Detailed Dissection of UBE3A-Mediated DDI1 Ubiquitination

“…The regulation of the enzymes modulating protein PTMs is crucial for maintaining the appropriate balance of protein modification required for cellular homeostasis. In fact, as already mentioned, deregulation of these enzymes is implicated in a number of diseases, including cancer and rare neurological diseases (Ruprecht and Lemeer, 2014; Osinalde et al, 2018). Therefore, emerging therapeutic strategies are focused on the design of drugs that modify the biological action of these enzymes, and consequently restore appropriate cellular PTM levels.…”