UCH‐L1 aggresome formation in response to proteasome impairment indicates a role in inclusion formation in Parkinson's disease

Abstract

Aggresomes are associated with many neurodegenerative disorders, including Parkinson's disease, and polyglutamine disorders such as Huntington's disease. These inclusions commonly contain ubiquitylated proteins. The stage at which these proteins are ubiquitylated remains unclear. A malfunction of the ubiquitin/proteasome system (UPS) may be associated with their formation. Conversely, it may reflect an unsuccessful attempt by the cell to remove them. Previously, we demonstrated that overexpression of Parkin, a ubiquitinprotein ligase associated with autosomal recessive juvenile Parkinsonism, generates aggresome-like inclusions in UPS compromised cells. Mutations in the de-ubiquitylating enzyme, UCH-L1, cause a rare form of Parkinsonism. We now demonstrate that overexpression of UCH-L1 also forms ribbon-like aggresomes in response to proteasomal inhibition. Diseaseassociated mutations, which affect enzymatic activities, significantly increased the number of inclusions. UCH-L1 aggresomes co-localized with ubiquitylated proteins, HSP70, c-tubulin and, to a lesser extent, the 20S proteasome and the chaperone BiP. Similar to Parkin inclusions, we found UCH-L1 aggresomes to be surrounded by a tubulin rather than a vimentin cage-like structure. Furthermore, UCH-L1 aggregates with Parkin and a-synuclein in some, but not all inclusions, suggesting the heterogeneous nature of these inclusion bodies. This study provides additional evidence that aggregation-prone proteins are likely to recruit UPS components in an attempt to clear proteins from failing proteasomes. Furthermore, UCH-L1 accumulation is likely to play a pathological role in inclusion formation in Parkinson's disease.

Allele-specific silencing of mutant Ataxin-7 in SCA7 patient-derived fibroblasts

“…34 Decreases in its expression, resulting in impairment of the ubiquitin proteasome pathway, have been linked to several neurodegenerative disorders, including Parkinson disease, Alzheimer's disease and HD. [35][36][37] Furthermore, a mouse model with a loss-of-function UCHL1 deletion displays an ataxic phenotype, 38,39 validating the changes seen in SCA7 patient cells.…”

Proteomic Analysis of Mice Hippocampus in Simulated Microgravity Environment

“…26 Down-regulation of PEBP may result in lower levels of HCNP or altered coordination of signal transduction pathways that may contribute to neuronal dysfunction and pathogenesis as observed in Alzheimer disease. 27 In the hippocampus, a decrease in PEBP under simulated microgravity may therefore lead to neuronal dysfunction, mainly in relaying signal from the membrane to the cytoplasm which is one of the function of this protein predicted based on its structure. 28 Pgam 1 protein is represented high in simulated microgravity in the hippocampus and is involved in glucose metabolism in the brain (Figure 1 Spot 17).…”

Altered gene expression in cells from patients with lysosomal storage disorders suggests impairment of the ubiquitin pathway

“…However, reduction of UCH-L1 also suppresses deubiquitination of monoubiquitinated proteins before their degradation within the endosomal-lysosomal pathway and may cause an opposite effect: reduction of the mUb concentration in the cell below the critical level necessary to maintain the proteosomal activity. A recent paper by Ardley et al 35 describes an increased level of aggresomes after overexpression of a UCH-L1 variant bearing a I93M mutation that has reduced hydrolase activity in two siblings with Parkinson disease. 19 This result is reflective of the reduced UCH-L1 protein and hydrolase activity accompanying proteasomal inhibition and ubiquitin aggregate formation in our study.…”