The induction of Rrs1 expression is one of the earliest events detected in a presymptomatic knock-in mouse model of Huntington disease (HD). Rrs1 up-regulation fulfills the HD criteria of dominance, striatal specificity, and polyglutamine dependence. Here we show that mammalian Rrs1 is localized both in the nucleolus as well as in the endoplasmic reticulum (ER) of neurons. This dual localization is shared with its newly identified molecular partner 3D3/lyric. We then show that both genes are induced by ER stress in neurons. Interestingly, we demonstrate that ER stress is an early event in a presymptomatic HD mouse model that persists throughout the life span of the rodent. We further show that ER stress also occurs in postmortem brains of HD patients.

The efficacy of antibody-based immunotherapy is due to the activation of apoptosis, the engagement of antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity (CDC). We developed a novel strategy to enhance CDC using bispecific antibodies (bsAbs) that neutralize the C-regulators CD55 and CD59 to enhance C-mediated functions. Two bsAbs (MB20/55 and MB20/59) were designed to recognize CD20 on one side. The other side neutralizes CD55 or CD59. Analysis of CDC revealed that bsAbs could kill 4-25 times more cells than anti-CD20 recombinant antibody in cell lines or cells isolated from patients with chronic lymphocytic leukemia. The pharmacokinetics of the bsAbs was evaluated in a human-SCID model of Burkitt lymphoma. The distribution profile of bsAbs mimics the data obtained by studying the pharmacokinetics of anti-CD20 antibodies, showing a peak in the tumor mass 3-4 days after injection. The treatment with bsAbs completely prevented the development of human/SCID lymphoma. The tumor growth was blocked by the activation of the C cascade and by the recruitment of macrophages, polymorphonuclear and natural killer cells. This strategy can easily be applied to the other anti-tumor C-fixing antibodies currently used in the clinic or tested in preclinical studies using the same vector with the appropriate modifications.

Mutations in PARK7 DJ-1 have been associated with autosomal-recessive early-onset Parkinson's disease (PD). This gene encodes for an atypical peroxiredoxin-like peroxidase that may act as a regulator of transcription and a redox-dependent chaperone. Although large gene deletions have been associated with a loss-of-function phenotype, the pathogenic mechanism of several missense mutations is less clear. By performing a yeast two-hybrid screening from a human fetal brain library, we identified TRAF and TNF receptor-associated protein (TTRAP), an ubiquitin-binding domain-containing protein, as a novel DJ-1 interactor, which was able to bind the PD-associated mutations M26I and L166P more strongly than wild type. TTRAP protected neuroblastoma cells from apoptosis induced by proteasome impairment. In these conditions, endogenous TTRAP relocalized to a detergent-insoluble fraction and formed cytoplasmic aggresome-like structures. Interestingly, both DJ-1 mutants blocked the TTRAP protective activity unmasking a c-jun N-terminal kinase (JNK)-and p38-MAPK (mitogen-activated protein kinase)-mediated apoptosis. These results suggest an active role of DJ-1 missense mutants in the control of cell death and position TTRAP as a new player in the arena of neurodegeneration. Cell Death and Differentiation (2009) Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder, affecting 1-2% of all individuals above the age of 65 years. Its neuropathological hallmark is the selective degeneration of subsets of mesencephalic dopaminergic cells and the formation of proteinaceous cytoplasmic aggregates called Lewy bodies. 1 Several studies implicate the ubiquitin-proteasome system in PD pathogenesis. 2 Synthetic proteasome inhibitors preferentially affect catecholaminergic neurons, leading to cell death. Furthermore, key ubiquitin-proteasome system elements are altered in PD post-mortem brains. [3][4][5] The identification of genes (PARK1-14) associated with familial PD has provided crucial insights into the pathogenic mechanisms. 1 The ubiquitin ligase parkin (PARK2) and the ubiquitin C-terminal hydrolase-L1 (UCH-L1) (PARK5) have been implicated in the ubiquitin-proteasome system function. Interestingly, upon treatment with proteasome inhibitors, they formed insoluble aggregates and were recruited to a juxtanuclear aggresome-like inclusion that resembled the Lewy body. 6,7 Autosomal-recessive early-onset PD has been associated with mutations in PARK7/DJ-1. 8 Functional DJ-1 is a dimer that acts as an atypical peroxiredoxin-like peroxidase as well as a regulator of transcription and a chaperone. 9-12 Interestingly, ectopic DJ-1 expression protects cells from death induced by a variety of insults. 13 DJ-1 loss in humans causes PD. 14 DJ-1 knock-out (KO) mice and flies showed increased vulnerabilities to neurotoxic agents but no signs of dopaminergic cell death. [15][16][17] PD families may also present missense mutations of DJ-1 in homozygous (L166P, M26I and E64D) and heterozygous forms (A104T and D149A)....

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