Protein degradation in Parkinson disease revisited: it’s complex

Abstract

Parkinson disease (PD) is the second most common neurodegenerative disorder, and mutations in the genes PTEN-induced putative kinase 1 (PINK1, also known as Parkinson disease 6 [PARK6]), PARKIN (also known as PARK2), and DJ-1 (also known as PARK7) cause autosomal recessive forms of PD/parkinsonism. PINK1 encodes a protein with a mitochondrial targeting sequence and a putative serine/threonine kinase domain, and PINK1 is predominantly localized to mitochondria (1). The Parkin protein contains two RING finger motifs, has E3 ubiquitin ligase activity in vitro, and is largely localized to the cytosol (1). The endogenous DJ-1 protein is found in mitochondria and cytosol, but the function of DJ-1 is not entirely clear (1). Studies on the functions of these genes may provide important insights into PD pathogenesis. Prior studies on protein degradationMost PD patients have intraneuronal inclusions in the form of ubiquitin-positive Lewy bodies and Lewy neurites. Given the presence of Parkin in Lewy bodies and the putative role of Parkin as an E3 ligase, much of the initial work on Parkin was focused on its potential role in regulating protein degradation via the ubiquitin-proteasome system (UPS). Ubiquitination is accomplished by covalently linking the ubiquitin polypeptide (Ub) to a lysine residue in a specific protein substrate and requires the sequential action of an E1 activating enzyme, an E2 conjugating enzyme, and an E3 ligase (2). E3 ubiquitin ligases can mediate monoubiquitination (the addition of a single Ub to the substrate protein), multiubiquitination (the addition of multiple single Ubs to different lysine residues in a target protein), and polyubiquitination (in which chains of four or more Ubs are formed by the linkage of Ub molecules to lysine residues in other Ub molecules) (2). These linkages are most often to lysine 48 (K48) or lysine 63 (K63) of the Ub polypeptide. Proteins to be degraded by the proteasome are largely K48 polyubiquitinated. In contrast, K63 polyubiquitination, as well as monoubiquitination and multiubiquitination, primarily function in non-degradative processes including signal transduction, transcriptional regulation, protein localization, and membrane trafficking (2).Previous studies suggested that Parkin could function as an E3 ligase for proteasome-mediated protein degradation (3). A handful of substrates of Parkin, including Parkin itself and an a-synuclein-interacting protein (Synphilin-1) (4), have been identified in vitro. If Parkin were indeed important in the degradative pathway in vivo, one would expect that the levels of its substrates should increase in Parkinknockout mice. Unexpectedly, however, most of the substrates studied, including Synphilin-1, did not accumulate in Parkinnull mice (5). In addition, several studies have revealed that Parkin preferentially catalyzes monoubiquitination and K63-linked polyubiquitination of substrates including Synphilin-1 (6-8). These latter observations may offer potential explanations for the lack of substrate accumulation in vivo b...

Methylmercury can induce Parkinson’s-like neurotoxicity similar to 1-methyl-4- phenylpyridinium: a genomic and proteomic analysis on MN9D dopaminergic neuron cells

“…Moreover, a dysfunctional proteo-somal degradation pathway (Fig. 1A and C) has been suggested to be involved in the neurodegenerative process of PD and mercury neurotoxicity (Li and Guo, 2009;Lim and Tan, 2007;Yu et al, 2010). Our results confirmed that the ubiquitin-proteasome system was a common target affected by both MeHg and MPP + treatments.…”

Protein Expression Regulation under Oxidative Stress

“…Negative and positive t values indicate depletion and enrichment of the feature in the test set, respectively. ͓T͔ [5][6][7][8][9][10] and ͓TA͔ 3-6 are binding motifs for the poly(A)-binding proteins Pub1 and Pab1, respectively (54). AUC, area under curve (where the curve is the receiver-operator characteristic), the closer to 1 the better is the prediction; PARS, parallel analysis of RNA structure, i.e.…”

“…son's disease (6), and cardiovascular disease (7). Moreover, protein aggregation is related to the impairment of the ubiquitin proteasome system, and both processes are hallmarks of several neurodegenerative diseases (8,9).…”

Parkin Ubiquitinates Drp1 for Proteasome-dependent Degradation

“…A handful of substrates have been identified, including Parkin itself and CDCrel-1, synphilin-1, Pael-R, glycosylated ␣-synuclein, FBP1 (far upstream elementbinding protein 1), and the RNA-processing protein subunit p38/AIMP2 (16 -19). A putative mechanism by which mutations of Parkin cause PD would be abnormal accumulation and aggregation of the above substrates due to insufficient E3 ligase activity for ubiquitin-proteasome-dependent protein turnover (18,20,21). Surprisingly, only p38/AIMP2 and FBP1 were found to be accumulated in the brain samples of PD patients or in Parkin knock-out mice (16,17,19).…”