Functions of DJ-1

Subject: Functions of DJ-1

Date: 6/13/2005

1. Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial parkinsonism-linked gene DJ-1
MS Goldberg, A Pisani, M Haburcak, TA Vortherms, G Martella, A Tscherter, A Martins, G Bernardi, BL Roth, EN Pothos, P Calabresi, J Shen
Neuron 2005;45:489-496

Lack of DJ-1 reduces synaptic dopamine, reduces responsiveness to D2 autoreceptor stimulation, and causes hypoactivity in mice, according to this report.

DJ-1 double-knockout mice were examined. Results for these mice showed:

--normal gross tissue histology and normal numbers of nigral dopamine neurons, no increased sensitivity to paraquat, normal total striatal dopamine, normal dopamine turnover, and normal tyrosine hydroxylase activity.

--To determine the effect of DJ-1 loss on dopaminergic neurotransmission, striatal slices were stimulated and dopamine overflow was measured. Dopamine overflow, which is determined by the balance of release and reuptake, was reduced sixfold compared to normal mice. This effect could be mitigated by blocking reuptake, “suggesting that increased dopamine reuptake primarily accounts for the reduced evoked dopamine overflow” in DJ1-null mice.

--In response to high-frequency stimulation, long-term potentiation was normal, but long-term depression was reduced, an effect that could be reversed by coadministration of a D2-specific agonist. A D1-specific agonist had no effect.

--Voluntary movement was markedly reduced in several aspects, an effect the authors suggest may be related to the reduced synaptic dopamine.

“These observations suggest that DJ-1 is required for normal D2R-dependent regulation of dopamine reuptake in the presynaptic terminals of nigral neurons,” the authors conclude. “Our data support an important role for DJ-1 in regulation of the excitability and firing of nigral dopaminergic neurons, which is an important determinant of the output of nigrostriatal projections.”

A Preview by Emiliana Borelli accompanies the report.

2. The Parkinson’s disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis
J Xu, N Zhong, H Wang, JE Elias, CY Kim, I Woldman, C Pifl, SP Gygi, C Geula, BA Yanker
Human Mol Genetics 2005;14:1231-1241

The identity of two binding partners for DJ-1 suggest it plays a role in transcriptional regulation and protection from apoptosis, according to this study.

The function of DJ-1 and the consequences of its absence were examined in dopaminergic cell culture. Results showed:

--human wild-type DJ-1 binds to nuclear RNA binding protein p54nrb, and to pyrimidine tract-binding protein-associated splicing factor (PSF). The three proteins colocalized in the nucleus.

--pathogenic DJ-1 mutants, but not a nonpathogenic polymorphic DJ-1, exhibited reduced nuclear distribution and co-localization with p54nrb and PSF. Mutant DJ-1 was increased in mitochondria. Mutant proteins were also less stable than wild-type.

--Wild-type, but not mutant, DJ-1, reversed the repression transcription that is a normal function of PSF. This effect appeared to be mediated by binding of DJ-1 to p54nrb.

--In cells exposed to dopamine, exposure to PSF increased apoptosis. This effect could be reversed by wild-type or polymorphic DJ-1, but not mutant DJ-1. The loss of protection from apoptosis by mutant DJ-1 could be mimicked by siRNA directed against wild-type DJ-1, indicating the mutant acts through a loss of function.

--Co-transfection of dopaminergic cells wild-type DJ-1 protected cells against mutant alpha-synuclein-induced apoptosis. This effect did not occur with mutant DJ-1. Overexpression of p54nrb also protected cells from mutant alpha-synuclein.

The authors conclude, “DJ-1 is a neuroprotective transcriptional co-activator that may act in concert with p54nrb and PSF to regulate the expression of a neuroprotective genetic program. Mutations that impair the transcriptional co-activator function of DJ-1 render dopaminergic neurons vulnerable to apoptosis and may contribute to the pathogenesis of PD.”

3. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and oxidative stress
RH Kim, PD Smith, H Aleyasin, S Hayley, MP Mount, S Pownall, A Wakeham, AJ You-Ten, SK Kalia, P Horne, D Westaway, AM Lozano, H Anisman, DS Park, TW Mak
PNAS 2005;102:5215-5220

Lack of DJ-1 increases sensitivity to oxidative stress, according to this study.

Study of DJ-1 knockout mice showed:

--knockout mice had no decrease in voluntary movement compared to wild-type mice.

--cultured neurons without DJ-1 were 20% more susceptible to H2O2 stress than normal neurons, an effect that could be rescued by adenovirally delivered DJ-1. Neurons lacking DJ-1 were also more sensitive to rotenone.

--dopaminergic neurons in vivo in knockout mice were more sensitive to MPTP, an effect that could be rescued by adenovirally delivered DJ-1.