Abstract
Mutations in PARK7/DJ-1 gene are associated to autosomal recessive early onset forms of Parkinson's disease (PD). Although large gene deletions have been linked to a loss-of-function phenotype, the pathogenic mechanism of missense mutations is less clear. The L166P mutation causes misfolding of DJ-1 protein and its degradation. L166P protein may also accumulate into insoluble cytoplasmic aggregates with a mechanism facilitated by the E3 ligase TNF receptor associated factor 6 (TRAF6). Upon proteasome impairment L166P activates the JNK/p38 MAPK apoptotic pathway by its interaction with TRAF and TNF Receptor Associated Protein (TTRAP). When proteasome activity is blocked in the presence of wild-type DJ-1, TTRAP forms aggregates that are localized to the cytoplasm or associated to nucleolar cavities, where it is required for a correct rRNA biogenesis. In this study we show that in post-mortem brains of sporadic PD patients TTRAP is associated to the nucleolus and to Lewy Bodies, cytoplasmic aggregates considered the hallmark of the disease. In SH-SY5Y neuroblastoma cells, misfolded mutant DJ-1 L166P alters rRNA biogenesis inhibiting TTRAP localization to the nucleolus and enhancing its recruitment into cytoplasmic aggregates with a mechanism that depends in part on TRAF6 activity. This work suggests that TTRAP plays a role in the molecular mechanisms of both sporadic and familial PD. Furthermore, it unveils the existence of an interplay between cytoplasmic and nucleolar aggregates that impacts rRNA biogenesis and involves TRAF6.
Highlights
The accumulation of misfolded proteins is a common feature to a wide range of neurodegenerative diseases [1]
Mutant DJ-1 may accumulate into insoluble cytoplasmic aggregates [14,15] and acquire a gainof-function property that may co-exist with its loss of physiological activity, as previously found for mutant HTT in Huntington’s disease (HD) [16] and superoxide dismutase 1 (SOD1) missense mutations in amyotrophic lateral sclerosis (ALS) [17]
These data show that TNF Receptor Associated Protein (TTRAP) is present in cytoplasmic Lewy Bodies (LBs) as well as in the nucleolus in surviving dopaminergic neurons of sporadic Parkinson’s disease (PD) brains
Summary
The accumulation of misfolded proteins is a common feature to a wide range of neurodegenerative diseases [1]. In Huntington’s disease (HD), N-terminal fragments of mutant huntingtin (N-HTT) form intracellular aggregates in the brain [2]. DJ-1 is a ubiquitously expressed protein that is mutated in autosomal recessive early onset forms of PD (PARK7) [7]. Mutant DJ-1 may accumulate into insoluble cytoplasmic aggregates [14,15] and acquire a gainof-function property that may co-exist with its loss of physiological activity, as previously found for mutant HTT in HD [16] and superoxide dismutase 1 (SOD1) missense mutations in amyotrophic lateral sclerosis (ALS) [17]
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