Phenylbutyrate Up-regulates the DJ-1 Protein and Protects Neurons in Cell Culture and in Animal Models of Parkinson Disease

Abstract

Parkinson disease is caused by the death of midbrain dopamine neurons from oxidative stress, abnormal protein aggregation, and genetic predisposition. In 2003, Bonifati et al. (23) found that a single amino acid mutation in the DJ-1 protein was associated with early-onset, autosomal recessive Parkinson disease (PARK7). The mutation L166P prevents dimerization that is essential for the antioxidant and gene regulatory activity of the DJ-1 protein. Because low levels of DJ-1 cause Parkinson, we reasoned that overexpression might stop the disease. We found that overexpression of DJ-1 improved tolerance to oxidative stress by selectively up-regulating the rate-limiting step in glutathione synthesis. When we imposed a different metabolic insult, A53T mutant ␣-synuclein, we found that DJ-1 turned on production of the chaperone protein Hsp-70 without affecting glutathione synthesis. After screening a number of small molecules, we have found that the histone deacetylase inhibitor phenylbutyrate increases DJ-1 expression by 300% in the N27 dopamine cell line and rescues cells from oxidative stress and mutant ␣-synuclein toxicity. In mice, phenylbutyrate treatment leads to a 260% increase in brain DJ-1 levels and protects dopamine neurons against 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) toxicity. In a transgenic mouse model of diffuse Lewy body disease, long-term administration of phenylbutyrate reduces ␣-synuclein aggregation in brain and prevents age-related deterioration in motor and cognitive function. We conclude that drugs that up-regulate DJ-1 gene expression may slow the progression of Parkinson disease by moderating oxidative stress and protein aggregation. Dopamine cell death in Parkinson disease (PD)3 results from both genetic and environmental factors (1-5). Six genes have been linked to PD including ␣-synuclein, Parkin, UCHL1, DJ-1, PINK1, and LRRK2 (6 -7). ␣-Synuclein mutations (A53T, A30P, and E46K) cause autosomal dominant forms of PD (8 -10). Even in sporadic cases of PD, aggregated ␣-synuclein has been found to be a major component of Lewy bodies (11-13). The toxicity of mutant forms of ␣-synuclein results from increased formation of oligomeric and fibrillar aggregates (14 -17). We and others (18 -22) have demonstrated that expression of A53T mutant ␣-synuclein results in protein aggregation and cell death in cultured dopamine neurons.Mutations in the DJ-1 gene (PARK7) lead to early-onset, autosomal recessive Parkinson disease (23-26). Ordinarily, DJ-1 protects cells by a number of mechanisms. The protein can self-oxidize by forming cysteine-sulfinic acid under oxidizing conditions, thereby shifting its pI from 6.1 to 5.8 (27-28). DJ-1 can sequester the cell death protein Daxx and prevent Daxx-induced apoptosis after oxidative stress (29). DJ-1 can stabilize Nrf2 (nuclear factor erythroid 2-related factor) by preventing association with its inhibitor protein, Keap1, thereby blocking the subsequent ubiquitination of Nrf2 (30).Previously, we have reported that overexpression of WT DJ-1 can prote...

Epigenetic Landscape of Parkinson's Disease: Emerging Role in Disease Mechanisms and Therapeutic Modalities

“…HDAC inhibitors are also known to modulate important cytoprotective pathways independent of their actions on histones, providing additional beneficial effects to therapy. For instance, 4PBA has been demonstrated to protect DA neurons, possibly via increased DJ-1 expression and the activation of the tyrosine hydroxylase promoter in the substantia nigra [79]. In another study, 4PBA was found to alter gene transcription in a number of genes associated with antioxidant enzyme chaperones, including those that are critical for cell survival [80].…”

Catechol Tetrahydroisoquinolines Enhance a-Synuclein Aggregation and Specify the Neurotoxicity to Dopaminergic Neurons

“…Secondly, histone modification is also an important mechanism of α-syn aggregation, and its effect mainly focuses on the histone acetylation [121]. Recently, the team from Freed, presented that long-term administration of a histone deacetylase (HDAC) inhibitor, phenylbutyrate, reduced α-syn aggregation in the brain and improved motor and cognitive function in aged transgenic mice expressing a tyrosine to cysteine mutant human α-syn [122]. Similarly, Valproic acid, an inhibitor of histone deacetylase, counteracted the alteration of α-syn, the death of nigral neurons and the declined levels of striatal DA in the rotenone-treated rats [123].…”

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.…”