Hsp70 Gene Transfer by Adeno-associated Virus Inhibits MPTP-Induced Nigrostriatal Degeneration in the Mouse Model of Parkinson Disease

Dong, Zhizhong; Wolfer, David P; Lipp, Hans‐Peter; Büeler, Hansruedi

doi:10.1016/j.ymthe.2004.09.007

Cited by 133 publications

(107 citation statements)

References 62 publications

Supporting

Mentioning

100

Contrasting

Unclassified

Order By: Relevance

“…That increase was blocked when native DJ-1 was reduced by AS DJ-1. Others have shown that increased Hsp70 can reduce ␣-synuclein protein aggregation and toxicity in Drosophila (41,42), mouse (43,44), and cell culture models (45,46). Hsp70 preferentially binds and stabilizes ␣-synuclein protofibrils, which results in inhibition of larger ␣-synuclein aggregates and cell toxicity (47).…”

Section: Discussionmentioning

confidence: 99%

DJ-1 Up-regulates Glutathione Synthesis during Oxidative Stress and Inhibits A53T α-Synuclein Toxicity

Zhou

Freed

2005

Journal of Biological Chemistry

329

295

View full text Add to dashboard Cite

DJ-1 is the third gene that has been linked to Parkinson disease.Mutations in the DJ-1 gene cause early onset PD with autosomal recessive inheritance. To clarify the mechanism of DJ-1 protection, we have overexpressed the gene in cultured dopaminergic cells that were then subjected to chemical stress. In the rat dopaminergic cell line, N27, and in primary dopamine neurons, overexpression of wild type DJ-1 protected cells from death induced by hydrogen peroxide and 6-hydroxydopamine. Overexpressing the L166P mutant DJ-1 had no protective effect. By contrast, knocking down endogenous DJ-1 with antisense DJ-1 rendered cells more susceptible to oxidative damage. We have found that DJ-1 improves survival by increasing cellular glutathione levels through an increase in the rate-limiting enzyme glutamate cysteine ligase. Blocking glutathione synthesis eliminated the beneficial effect of DJ-1. Protection could be restored by adding exogenous glutathione. Wild type DJ-1 reduced cellular reactive oxygen species and reduced the levels of protein oxidation caused by oxidative stress. By a separate mechanism, overexpressing wild type DJ-1 inhibited the protein aggregation and cytotoxicity usually caused by A53T human ␣-synuclein. Under these circumstances, DJ-1 increased the level of heat shock protein 70 but did not change the glutathione level. Our data indicate that DJ-1 protects dopaminergic neurons from oxidative stress through up-regulation of glutathione synthesis and from the toxic consequences of mutant human ␣-synuclein through increased expression of heat shock protein 70. We conclude that DJ-1 has multiple specific mechanisms for protecting dopamine neurons from cell death. Parkinson disease (PD)2 is a common neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra and by the presence of intracellular inclusions called Lewy bodies (1, 2). The etiology of PD may involve both genetic and environmental factors (3). In recent years, several genes linked to PD have been discovered. ␣-Synuclein was the first gene identified whose mutations, A53T and A30P, cause autosomal dominant forms of PD (4, 5). Importantly, aggregated ␣-synuclein has been found to be a major component of Lewy bodies (6). Mutations in a second gene, Parkin, cause early onset PD with autosomal recessive inheritance (7). Parkin is an ubiquitinprotein isopeptide ligase controlling protein degradation through the ubiquitin-proteasome system (8).DJ-1 is the third PD gene identified and is linked to early onset disease with autosomal recessive inheritance (9). Eleven different mutations have been found in the DJ-1 gene including missense, truncation, and splice site mutations as well as large deletions, suggesting that loss of DJ-1 function leads to neurodegeneration (9 -11). DJ-1 is a 189-amino acid protein with multiple functions (12). DJ-1 interacts with H-ras to increase cell transformation (13). DJ-1 is a regulatory subunit of an RNA-binding protein complex (14). Through binding to PIASx␣, the transcription...

show abstract

Section: Discussionmentioning

confidence: 99%

DJ-1 Up-regulates Glutathione Synthesis during Oxidative Stress and Inhibits A53T α-Synuclein Toxicity

Zhou

Freed

2005

Journal of Biological Chemistry

329

295

View full text Add to dashboard Cite

show abstract

“…ER and cellular stress marker proteins such as BiP and Hsp70 have been shown to have elevated expression levels in response to toxic stress in various neurodegenerative disorders, and many reports have detailed the relationship between JNK and Hsp70 (28,29,(33)(34)(35). Mitochondrial protein SOD1 has been implicated in ALS, and its activity is critical against oxidative stress, a hallmark of various neurodegenerative diseases (36).…”

Section: Overexpression Of Sgk1 In Sh-sy5y Cells Regulates 6-ohda-indmentioning

confidence: 99%

Serum- and Glucocorticoid-Inducible Kinase 1 Confers Protection in Cell-Based and in In Vivo Neurotoxin Models via the c-Jun N-Terminal Kinase Signaling Pathway

Iqbal

Howard

LoGrasso

2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

Serum glucocorticoid kinase 1 (SGK1) has been shown to be protective in models of Parkinson's disease, but the details by which it confers benefit is unknown. The current study was designed to investigate the details by which SGK1 confers neuroprotection. To do this we employed a cellular neurodegeneration model to investigate c-Jun N-terminal kinase (JNK) signaling and endoplasmic reticulum (ER) stress induced by 6-hydroxydopamine. SGK1-expressing adenovirus was created and used to overexpress SGK1 in SH-SY5Y cells, and dexamethasone was used to increase endogenous expression of SGK1. Oxidative stress, mitochondrial dysfunction, and cell death were monitored to test the protective effect of SGK1. To investigate the effect of SGK1 overexpression in vivo, SGK1-expressing adenovirus was injected into the striatum of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and protection of dopaminergic neurons was quantitatively assessed by tyrosine hydroxylase immunohistochemistry. SGK1 overexpression was found to decrease reactive oxygen species generation, alleviate mitochondrial dysfunction, and rescue cell death in vitro and in vivo by inactivating mitogen-activated protein kinase kinase 4 (MKK4), JNK, and glycogen synthase kinase 3␤ (GSK3␤) and thereby decreasing ER and oxidative stress. These results suggest that therapeutic strategies for activation of SGK1 may have the potential to be neuroprotective by deactivating the JNK and GSK3␤ pathways.S erum-and glucocorticoid-inducible kinase 1 (SGK1) belongs to the AGC family of kinases and has been shown to have various cellular functions, including the promotion of cell survival (1-3). SGK1 is activated by insulin and growth factors via phosphoinositide 3-kinase (PI3K), 3-phosphoinositide-dependent kinase 1 (PDK1), and mammalian target of rapamycin complex 2 (mTORC2) (4, 5). SGK1 shares its functions and some substrates with another kinase from the AGC family, protein kinase B (PKB/ Akt). Akt, like SGK1, has been shown to mediate cell survival through various signaling cascades and gets activated by a wide range of extracellular stimuli (6). SGK1 lacks the pleckstrin homology (PH) domain that tethers Akt to the plasma membrane, making SGK1 more accessible to cytosolic and nuclear sites and thereby providing it with cellular functions and substrates that do not overlap those of Akt (1, 6). SGK1 plays a protective role in oxidative stress conditions as small interfering RNA (siRNA) knockdown of SGK1 has shown an increase in oxidative stressinduced cell death in HEK293 cells (7). Oxidative stress is a hallmark of neurodegenerative disorders, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) (8). In a study published in 2005 by Schoenebeck et al., upregulation of SGK1 was seen in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model and in a transgenic model of ALS (SOD1-G93A), and protection from cell death was observed for animals treated with dexamethasone (De...

show abstract

“…The neurotoxicity of MPTP depends on the transformation of MPTP to its bioactive form MPP + , which is taken up into dopaminergic (DA) neurons by their DA transporters. MPP + inhibits mitochondrial complex I, leading to decreased ATP production, increased generation of reactive oxygen species, apoptosis, and endoplasmic reticulum stress due to accumulation of unfolded proteins (10,19,20).…”

Section: Discussionmentioning

confidence: 99%

“…The overexpression of Hsp70 has been shown to prevent dopaminergic neuronal loss associated with α-synuclein in Drosophila (9). Hsp70 gene transfer to the dopamine neurons by a recombinant adeno-associated virus also protected the mouse dopaminergic system against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced loss of dopaminergic neurons (10). Moreover, the induction of Hsp70 expression by prior exposure to heat shock offers some protection against 1-methyl, 4-phenyl, pyridinium ion (MPP)-induced neuronal cell death in cultured PC12 cells (11).…”

Section: Introductionmentioning

confidence: 99%

MPTP-induced model of Parkinson's disease in heat shock protein 70.1 knockout mice

et al. 2012

View full text Add to dashboard Cite

Abstract. Heat shock proteins (HSPs), molecular chaperones that assist in protein folding, have become a research focus in Parkinson's disease (PD) since the pathogenesis of PD is characterized by intracellular protein misfolding and inclusion body formation. This study investigated the effect of the knockout (KO) of the Hsp70.1 (approved gene symbol Hspa1b) gene on the sensitivity of murine nigrostriatal dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity. We confirmed changes in motor coordination and tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra following MPTP treatment of C57BL/6 normal mice and Hspa1b KO mice. MPTP treatment led to motor control impairment and induced TH-positive dopaminergic neurodegeneration in normal mice. Compared to untreated normal mice, rotarod duration and the density of TH-positive neurons in the substantia nigra were also significantly lower in untreated KO mice (p<0.01). MPTPtreated KO mice had markedly decreased rotarod duration and reduced density of TH-positive neurons, compared to MPTPtreated normal mice. These results indicate that Hspa1b KO mice are more vulnerable to the neurotoxic effects of MPTP and are consistent with the hypothesis that HSPs represent an important molecular target for neuroprotective strategies in the treatment of PD.

show abstract

Hsp70 Gene Transfer by Adeno-associated Virus Inhibits MPTP-Induced Nigrostriatal Degeneration in the Mouse Model of Parkinson Disease

Cited by 133 publications

References 62 publications

DJ-1 Up-regulates Glutathione Synthesis during Oxidative Stress and Inhibits A53T α-Synuclein Toxicity

DJ-1 Up-regulates Glutathione Synthesis during Oxidative Stress and Inhibits A53T α-Synuclein Toxicity

Serum- and Glucocorticoid-Inducible Kinase 1 Confers Protection in Cell-Based and in In Vivo Neurotoxin Models via the c-Jun N-Terminal Kinase Signaling Pathway

MPTP-induced model of Parkinson's disease in heat shock protein 70.1 knockout mice

Contact Info

Product

Resources

About