DJ-1 and Parkin Modulate Dopamine-dependent Behavior and Inhibit MPTP-induced Nigral Dopamine Neuron Loss in Mice

Abstract

Parkin-deficient animals exhibit mitochondrial degeneration and increased oxidative stress vulnerability, and both mice and flies lacking DJ-1 are hypersensitive to environmental toxins associated with Parkinson's disease (PD). We used recombinant adeno-associated virus (AAV) gene transfer to study the influence of DJ-1 and Parkin on the dopaminergic system of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, a model for sporadic PD. After MPTP lesioning, significantly more dopamine neurons survived in the virus-injected substantia nigra of the AAV-DJ-1 and AAV-Parkin mice when compared with AAV-enhanced green fluorescent protein injected controls. Protection at the neuronal level was supported by increased amphetamine-induced contralateral turning behavior. Normal mice expressing DJ-1 showed apomorphine-induced ipsilateral turning, suggesting a hyporesponsiveness of striatal dopamine D1 receptors in the DJ-1-expressing hemisphere. MPTP drastically reduced dopamine to 19% of normal levels and neither DJ-1 nor Parkin protected against MPTP-induced catecholamine loss under these conditions. Our results show that Parkin and DJ-1 inhibit dopamine neuron death and enhance amphetamine-induced dopaminergic function in a mouse model of idiopathic PD. However, DJ-1 overexpression also reduced postsynaptic dopamine receptor responses in normal mice. These results warrant further exploration of DJ-1 and Parkin gene therapy for PD, although a better understanding of their effects on behavior and dopamine neurotransmission is required before these proteins can be safely used.

Transduced Tat-DJ-1 Protein Protects against Oxidative Stress-Induced SH-SY5Y Cell Death and Parkinson Disease in a Mouse Model

“…Also, overexpression of DJ-1 reduced postsynaptic dopamine receptor responses in normal mice. These results suggest that further exploration of the molecular functions of DJ-1 for in vitro and in vivo is warranted before DJ-1 therapy for PD can commence (Paterna et al, 2007). In agreement with our results, transduced Tat-DJ-1 protein markedly decreased MPTP-induced TH neuron loss in mice.…”

“…However, the precise mechanisms remain to be studied further. Paterna et al (2007) has shown that overexpression of DJ-1 significantly reduces MPTP-induced TH neuron loss in mice. Although the mechanism is unclear, overexpression of DJ-1 may reduce DAT functions which contribute to the increased resistance of DJ-1 expression dopamine neurons against MPTP.…”

Advances in Gene Therapy for Movement Disorders

“…[83][84][85] Furthermore, viral vector-mediated PARK2 delivery prevents dopamine neuron loss induced by 6-OHDA and MPTP. 86,87 These findings taken together suggest that PARK2 delivery may be therapeutically beneficial not only in familial PD patients but also in sporadic PD.…”

Animal Models of Parkinson's Disease: A Gateway to Therapeutics?

“…Down-regulation of DJ-1 has been shown to increase the susceptibility to oxidative stress and proteasome inhibition [91,92].DJ-1 also acts as a redoxdependent chaperone molecule and inhibits α-synuclein aggregation [93]. Over-expression of DJ-1 protects against MPTP-induced neurodegeneration, indicating that the augmented expression of DJ-1 in response to the toxins is probably a helpful mechanism in fighting against the increased oxidative stress [94,95]. Knockout models of DJ-1 mice with a targeted deletion of exon 2 or insertion of a premature stop codon in exon 1 are more sensitive to toxins and oxidative stress.…”