Parkinson’s disease [PD], a progressive neurodegenerative disease, results in abnormal accumulation of insoluble alpha-synuclein [α-Syn] in dopaminergic neurons. Here we examined tauopathic changes and the α-Syn/p-GSK-3β/proteasome pathway in postmortem striata and inferior frontal gyri [IFG] from patients with PD and PD with dementia [PDD]. In both PD and PDD, α-Syn levels were high, especially the insoluble form of this protein; in PDD, insoluble α-Syn levels were persistently higher than PD across both brain regions. Levels of p-GSK-3β phosphorylated at Tyr 216, which hyperphosphorylates Tau to produce toxic pathological forms of p-Tau, were higher in striata of both PD and PDD compared to controls, but were unaltered in IFG. While proteasomal activity was unchanged in striatum of PD and PDD, such activity was diminished in the IFG of both PD and PDD. A decrease in 19S subunit of the proteasomes was seen in IFG of PDD, while lower levels of 20S subunits were seen in striatum and IFG of both PD and PDD patients. Parkin levels were similar in PD and PDD, suggesting lack of involvement of this protein. Most interestingly, tauopathic changes were noted only in striatum of PD and PDD, with increased hyperphosphorylation seen at Ser262 and Ser396/404; increases in Ser202 levels were seen only in PD but not in PDD striatum. We were unable to detect any tauopathy in IFG in either PD or PDD despite increased levels of α-Syn, and decreased proteasomal activity, and is probably due to lack of increase in p-GSK-3β in IFG. Unlike Alzheimer’s disease where tauopathy is more globally observed in diverse brain regions, our data demonstrates restricted expression of tauopathy in brains of PD and PDD, probably limited to dopaminergic neurons of the nigrostriatal region.

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V(D)J recombination, the rearrangement of gene segments to assemble Ig and T cell receptor coding regions, is vital to B and T lymphocyte development. Here, we demonstrate that the V(D)J recombinase protein RAG1 undergoes ubiquitylation in cells. In vitro, the RING finger domain of RAG1 acts as a ubiquitin ligase that mediates its own ubiquitylation at a highly conserved K residue in the RAG1 amino-terminal region. Ubiquitylation is best supported by a specific ubiquitin-conjugating enzyme, UbcH3͞CDC34, and requires an intact RAG1 RING finger motif. Disruption of the RING finger and certain RAG1 N-terminal truncations are associated with immunodeficiency in human patients, suggesting that RAG1's ubiquitin ligase is required for its biological role in lymphocyte development. The development of B and T cells depends on the rearrangement of variable (V), diversity (D), and joining (J) gene segments to produce mature Ig and T cell receptor coding regions (1). This rearrangement process, known as V(D)J recombination, must occur only in the correct lymphoid lineages and at the appropriate loci and developmental stages to minimize extraneous damage to the genome. Many factors are known to contribute to regulation of V(D)J recombination, and new evidence suggests that ubiquitin conjugation may also play an important role (2, 3).V(D)J recombination is initiated by the RAG1 and RAG2 gene products (4,5). Together these proteins act as a recombinase that introduces double-stranded DNA breaks at recombination signal sequences (RSSs) flanking the coding DNA (6, 7). The breaks are then repaired by the nonhomologous DNA end-joining machinery, resulting in fusions between pairs of coding gene segments and pairs of RSSs. Deletion analysis has defined minimal ''core'' regions of RAG1 and RAG2 (amino acids 384-1008 of 1,040 in RAG1 and 1-383 of 527 in RAG2) (8-11). A recombinase composed of core RAG1 and RAG2 retains DNA binding and cleavage activity in vitro and supports recombination of extrachromosomal V(D)J substrates (8,9,(12)(13)(14), although with some differences from the full-length recombinase (15-18). In vitro, core RAG1 and RAG2 are more active than their full-length counterparts in DNA transposition (15, 18), a potentially damaging reaction that could lead to RSS ends attacking other regions of the genome. The RAG2 core also displays a fundamental defect in recombination of the Ig heavy chain locus in the cell (19), apparently because of an inability to gain access to certain regions of the locus.Mutations of the ''dispensable'' regions of RAG1 also affect its activity. The RAG1 core can support D to J rearrangement at the Ig heavy chain locus in RAG1 Ϫ/Ϫ pro-B cells at a somewhat reduced level relative to the full-length protein, but deletions of smaller regions within the N terminus reduce chromosomal recombination considerably more (16). A naturally occurring RAG1 mutation that disrupts the conserved RING finger motif (C328Y) and two N-terminal truncation mutants have been found to be defective in B cell development...