Cao, S., Gelwix, C.C., Caldwell, K.A. & Caldwell, G.A. Torsin-mediated protection from cellular stress in the dopaminergic neurons of Caenorhabditis elegans. J. Neurosci. 25, 3801-3812

Department of Biological Sciences, University of Alabama, Tuscaloosa, Alabama, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 05/2005; 25(15):3801-12. DOI: 10.1523/JNEUROSCI.5157-04.2005
Source: PubMed


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 alpha-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 alpha-synuclein. Using mutant nematodes lacking DAT-1 function, we also showed that torsin neuroprotection from alpha-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.

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    • "Remarkably, C. elegans is ideal for such an investigation, because this anatomically and genetically defined transparent nematode has exactly 302 neurons, precisely eight of which are DA. This facilitates rapid scoring of DA neurodegeneration while worms age (Cao et al., 2005). Taking advantage of this system, we investigated the ability of GSK3b inhibitors to ameliorate the effects of a-synuclein overexpression and DA-specific toxicity. "
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    • "Animal models for DYT-TOR1A have been established for invertebrates (namely C. elegans and D. melanogaster) (Caldwell et al., 2003; Koh et al., 2004; Cao et al., 2005) which are suitable models for studying basic principles of the disease mechanisms on a multi-cellular level. However, the vast differences to the mammalian central nervous system limit the explanatory value for complex neuronal networks. "
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    ABSTRACT: Interneurons comprise a minority of the striatal neuronal population of roughly 5%. However, this heterogeneous population is of particular interest as it fulfills an important relay function in modulating the output of the only type of striatal projection neurons, i.e., the medium spiny neuron (MSN).One subtype of this heterogenous group, the cholinergic interneuron, is of particular scientific interest as there is a relevant body of evidence from animal models supporting its special significance in the disease process. The development of protocols for directed differentiation of human pluripotent stem cells (PSC) into striatal interneurons provides a unique opportunity to derive in vitro those cell types that are most severely affected in dystonia.In this review we first aim to give a concise overview about the normal function of striatal interneurons and their dysfunction in dystonia in order to identify the most relevant interneuronal subtype for the pathogenesis of dystonia. Secondly we demonstrate how knowledge about the embryonic development of striatal interneurons is of particular help for the development of differentiation protocols from PSC and by this depict potential ways of deriving in vitro disease models of dystonia. We furthermore address the question as to whether cell replacement therapies might represent a beneficial approach for the treatment of dystonia.
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    • "PD SNCA dat-1::human α-synuclein No obvious defect Dopamine neuron degeneration by expression of human α-synuclein specific in dopamine neuron (Lakso et al., 2003). dat-1::human α-synuclein No obvious defect Protective effect of TorsinA and Rab1 to against the α-synuclein toxicity (Cao et al., 2005; Cooper et al., 2006). dat-1::human α-synuclein No obvious defect Failure in modulation of locomotory rate in response to food (Kuwahara et al., 2006). "
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