Parkinson's disease (PD) is linked genetically to proteins that function in the management of cellular stress resulting from protein misfolding and oxidative damage. Overexpression or mutation of ␣-synuclein results in the formation of Lewy bodies and neurodegeneration of dopaminergic (DA) neurons. Human torsinA, mutations in which cause another movement disorder termed early-onset torsion dystonia, is highly expressed in DA neurons and is also a component of Lewy bodies. Previous work has established torsins as having molecular chaperone activity. Thus, we examined the ability of torsinA to manage cellular stress within DA neurons of the nematode Caenorhabditis elegans. Worm DA neurons undergo a reproducible pattern of neurodegeneration after treatment with 6-hydroxydopamine (6-OHDA), a neurotoxin commonly used to model PD. Overexpression of torsins in C. elegans DA neurons results in dramatic suppression of neurodegeneration after 6-OHDA treatment. In contrast, expression of either dystonia-associated mutant torsinA or combined overexpression of wild-type and mutant torsinA yielded greatly diminished neuroprotection against 6-OHDA. We further demonstrated that torsins seem to protect DA neurons from 6-OHDA through downregulating protein levels of the dopamine transporter (DAT-1) in vivo. Additionally, we determined that torsins protect robustly against DA neurodegeneration caused by overexpression of ␣-synuclein. Using mutant nematodes lacking DAT-1 function, we also showed that torsin neuroprotection from ␣-synuclein-induced degeneration occurs in a manner independent of this transporter. Together, these data have mechanistic implications for movement disorders, because our results demonstrate that torsin proteins have the capacity to manage sources of cellular stress within DA neurons.

Acute myocardial infarction (AMI) initiates an intense inflammatory response in which interleukin-1 (IL-1) plays a central role. The IL-1 receptor antagonist is a naturally occurring antagonist, and anakinra is the recombinant form used to treat inflammatory diseases. The aim of the present pilot study was to test the safety and effects of IL-1 blockade with anakinra on left ventricular (LV) remodeling after AMI. Ten patients with ST-segment elevation AMI were randomized to either anakinra 100 mg/day subcutaneously for 14 days or placebo in a doubleblind fashion. Two cardiac magnetic resonance (CMR) imaging and echocardiographic studies were performed during a 10-to 14-week period. The primary end point was the difference in the interval change in the LV end-systolic volume index (LVESVi) between the 2 groups on CMR imaging. The secondary end points included differences in the interval changes in the LV enddiastolic volume index, and C-reactive protein levels. A +2.0 ml/m 2 median increase (interquartile range +1.0, +11.5) in the LVESVi on CMR imaging was seen in the placebo group and a -3.2 ml/ m 2 median decrease (interquartile range -4.5, -1.6) was seen in the anakinra group (p = 0.033). The median difference was 5.2 ml/m 2 . On echocardiography, the median difference in the LVESVi change was 13.4 ml/m 2 (p = 0.006). Similar differences were observed in the LV enddiastolic volume index on CMR imaging (7.6 ml/m 2 , p = 0.033) and echocardiography (9.4 ml/m 2 , p = 0.008). The change in C-reactive protein levels between admission and 72 hours after admission correlated with the change in the LVESVi (R =+0.71, p = 0.022). In conclusion, in the present pilot study of patients with ST-segment elevation AMI, IL-1 blockade with anakinra was safe and favorably affected by LV remodeling. If confirmed in larger trials, IL-1 blockade might represent a novel therapeutic strategy to prevent heart failure after AMI.Acute myocardial infarction (AMI) initiates an intense inflammatory response characterized by an accumulation of leukocytes in the injured myocardium and the production of cytokines and chemokines, which further promotes adverse cardiac remodeling and heart failure. [1][2][3] Interleukin-1 (IL-1) is the prototypic inflammatory cytokine, inducing adhesion NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript molecules and chemokines. 4 IL-1 is also a known myocardial suppressant. [4][5] In AMI, IL-1 is initially released by the ischemic endothelial cells and cardiomyocytes and, later, by the leukocytes infiltrating the myocardium. 6 Although IL-1 leads to leukocyte recruitment, which contributes to infarct healing, IL-1 also promotes cell death in cardiomyocytes. 6,7 The naturally occurring IL-1 receptor antagonist binds to the IL-1 receptor and prevents IL-1 activity. 4 We have reported that a recombinant human IL-1 receptor antagonist, anakinra, ameliorated cardiac remodeling after a large anterior wall AMI in the experimental mouse model and improved survival. 7 Moreover, mice with...

Torsion dystonia is an autosomal dominant movement disorder characterized by involuntary, repetitive muscle contractions and twisted postures. The most severe early-onset form of dystonia has been linked to mutations in the human DYT1 (TOR1A) gene encoding a protein termed torsinA. While causative genetic alterations have been identified, the function of torsin proteins and the molecular mechanism underlying dystonia remain unknown. Phylogenetic analysis of the torsin protein family indicates these proteins share distant sequence similarity with the large and diverse family of AAA+ proteins. We have established the nematode, Caenorhabditis elegans, as a model system for examining torsin activity. Using an in vivo assay for polyglutamine repeat-induced protein aggregation in living animals, we have determined that ectopic overexpression of both human and C. elegans torsin proteins results in a dramatic reduction of polyglutamine-dependent protein aggregation in a manner similar to that previously reported for molecular chaperones. The suppressive effects of torsin overexpression persisted as animals aged, whereas a mutant nematode torsin protein was incapable of ameliorating aggregate formation. Antibody staining of transgenic animals indicated that both the C. elegans torsin-related protein TOR-2 and ubiquitin were localized to sites of protein aggregation. These data represent the first functional evidence of a role for torsins in effectively managing protein folding and suggest that possible breakdown in a neuroprotective mechanism that is, in part, mediated by torsins may be responsible for the neuronal dysfunction associated with dystonia.

Pharmacologic MyD88 inhibition protects against pathologic LV remodeling without altering infarct scar formation. MyD88 may be a viable target for pharmacologic inhibition in AMI.

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