Torsin-mediated protection from cellular stress in the dopaminergic neurons of Caenorhabditis elegans

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: 6.75). 05/2005; 25(15):3801-12. DOI: 10.1523/JNEUROSCI.5157-04.2005
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Guy A Caldwell, Aug 24, 2015
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurodegenerative diseases which include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington disease (HD), and others are becoming an increasing threat to human health worldwide. The degeneration and death of certain specific groups of neurons is the hallmark of these diseases. Despite the research progress in identification of several disease-related genes, the mechanisms underlying the neurodegeneration in these diseases remain unclear. Given the molecular conservation in neuronal signaling between Caenorhabditis elegans and vertebrates, increasing number of research scientists has used the nematode to study this group of diseases. This review paper will focus on the model system that has been established in Caenorhabditis elegans to investigate the pathogenetic roles of those reported disease-related genes in AD, PD, ALS, HD and others. The progress in Caenorhabditis elegans provides useful information of the genetic interactions and molecular pathways that are critical in the disease process, and may help our better understanding of the disease mechanisms and search for new therapeutics for these devastating diseases.
    Experimental Neurology 10/2013; 250. DOI:10.1016/j.expneurol.2013.09.024 · 4.62 Impact Factor
  • Source
    • "In Parkinson's disease (PD) and other synucleinopathies, accumulation of ␣-synuclein (␣syn ) in Lewy bodies is a pathological hallmark of disease (Spillantini et al., 1997). Missense mutations (A30P, A53T, E46K) and multiplications of the ␣-syn gene, in familial PD, enhance the propensity of ␣-syn to aggregate (Conway et al., 2000; Singleton et al., 2003) and overexpression of ␣-syn protein in various animal models of PD results in accumulation and neurotoxicity of ␣-syn (Masliah et al., 2000; Auluck et al., 2002; Cao et al., 2005). These findings suggest that accumulation of ␣-syn plays an important role in the pathogenesis of synucleinopathies and highlight ␣-syn clearance as a key therapeutic target. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The autophagy-lysosomal pathway plays an important role in the clearance of long-lived proteins and dysfunctional organelles. Lysosomal dysfunction has been implicated in several neurodegenerative disorders including Parkinson's disease and related synucleinopathies that are characterized by accumulations of α-synuclein in Lewy bodies. Recent identification of mutations in genes linked to lysosomal function and neurodegeneration has offered a unique opportunity to directly examine the role of lysosomes in disease pathogenesis. Mutations in lysosomal membrane protein ATP13A2 (PARK9) cause familial Kufor-Rakeb syndrome characterized by early-onset parkinsonism, pyramidal degeneration and dementia. While previous data suggested a role of ATP13A2 in α-synuclein misfolding and toxicity, the mechanistic link has not been established. Here we report that loss of ATP13A2 in human fibroblasts from patients with Kufor-Rakeb syndrome or in mouse primary neurons leads to impaired lysosomal degradation capacity. This lysosomal dysfunction results in accumulation of α-synuclein and toxicity in primary cortical neurons. Importantly, silencing of endogenous α-synuclein attenuated the toxicity in ATP13A2-depleted neurons, suggesting that loss of ATP13A2 mediates neurotoxicity at least in part via the accumulation of α-synuclein. Our findings implicate lysosomal dysfunction in the pathogenesis of Kufor-Rakeb syndrome and suggest that upregulation of lysosomal function and downregulation of α-synuclein represent important therapeutic strategies for this disorder.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 03/2012; 32(12):4240-6. DOI:10.1523/JNEUROSCI.5575-11.2012 · 6.75 Impact Factor
  • Source
    • "gregates comprising the toxic species in vivo remains unresolved , enhanced ␣ - syn expression has been con - clusively associated with neurotoxicity and PD ( Singleton et al . , 2003 ) . In C . elegans , transgenic overexpression of ␣ - syn leads to age - dependent ␣ - syn accumulation and dopaminergic neuron degeneration ( Lakso et al . , 2003 ; Cao et al . , 2005 ; Kuwahara et al . , 2006 ; Hamamichi et al . , 2008 ; van Ham et al . , 2008 ; Karpinar et al . , 2009 ) . Depletion of the E1 - like enzyme required for the initi - ation of autophagosome formation , atg - 7 , results in neurodegen - eration in mice ( Komatsu et al . , 2006 ) as well as enhanced ␣ - syn accumulation in C . elegans ( H"
    [Show abstract] [Hide abstract]
    ABSTRACT: Disruption of the lysosomal system has emerged as a key cellular pathway in the neurotoxicity of α-synuclein (α-syn) and the progression of Parkinson's disease (PD). A large-scale RNA interference (RNAi) screen using Caenorhabditis elegans identified VPS-41, a multidomain protein involved in lysosomal protein trafficking, as a modifier of α-syn accumulation and dopaminergic neuron degeneration (Hamamichi et al., 2008). Previous studies have shown a conserved neuroprotective function of human VPS41 (hVPS41) against PD-relevant toxins in mammalian cells and C. elegans neurons (Ruan et al., 2010). Here, we report that both the AP-3 (heterotetrameric adaptor protein complex) interaction domain and clathrin heavy-chain repeat domain are required for protecting C. elegans dopaminergic neurons from α-syn-induced neurodegeneration, as well as to prevent α-syn inclusion formation in an H4 human neuroglioma cell model. Using mutant C. elegans and neuron-specific RNAi, we revealed that hVPS41 requires both a functional AP-3 (heterotetrameric adaptor protein complex) and HOPS (homotypic fusion and vacuole protein sorting)-tethering complex to elicit neuroprotection. Interestingly, two nonsynonymous single-nucleotide polymorphisms found within the AP-3 interacting domain of hVPS41 attenuated the neuroprotective property, suggestive of putative susceptibility factors for PD. Furthermore, we observed a decrease in α-syn protein level when hVPS41 was overexpressed in human neuroglioma cells. Thus, the neuroprotective capacity of hVPS41 may be a consequence of enhanced clearance of misfolded and aggregated proteins, including toxic α-syn species. These data reveal the importance of lysosomal trafficking in maintaining cellular homeostasis in the presence of enhanced α-syn expression and toxicity. Our results support hVPS41 as a potential novel therapeutic target for the treatment of synucleinopathies like PD.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2012; 32(6):2142-53. DOI:10.1523/JNEUROSCI.2606-11.2012 · 6.75 Impact Factor
Show more