DJ-1( PARK7), a novel gene for autosomal recessive, early onset parkinsonism

Abstract

Four chromosomal loci ( PARK2, PARK6, PARK7, and PARK9) associated with autosomal recessive, early onset parkinsonism are known. We mapped the PARK7 locus to chromosome 1p36 in a large family from a genetically isolated population in the Netherlands, and confirmed this linkage in an Italian family. By positional cloning within the refined PARK7 critical region we recently identified mutations in the DJ-1 gene in the two PARK7-linked families. The function of DJ-1 remains largely unknown, but evidence from genetic studies on the yeast DJ-1 homologue, and biochemical studies in murine and human cell lines, suggests a role for DJ-1 as an antioxidant and/or a molecular chaperone. Elucidating the role of DJ-1 will lead to a better understanding of the pathogenesis of DJ-1-related and common forms of Parkinson's disease.

Stimulation of vesicular monoamine transporter 2 activity by DJ-1 in SH-SY5Y cells

“…Parkinson's disease [5,29], stimulated expression of the VMAT2 gene and VMAT2 activity. C106 mutant of DJ-1 also reduced stimulating activity toward VMAT2.…”

“…SH-SY5Y cells harboring a vector backbone were also established. M26I and L166P DJ-1 were found to be as homozygous mutations in Parkinson's disease patients [5,29]. Since cysteine at amino acid number 106 (C106)…”

“…Dopamine is a highly reactive molecule that is auto-oxidized to a quinone in the cytosol, and transport of dopamine into synaptic vesicles by VMAT2 prevents its autoxidation and subsequent degeneration of dopamine neurons. While most cases of PD are sporadic, 5-10% of PD patients carry mutations with a Mendelian inheritance, and mutations in parkin, DJ-1 and PINK1 genes have been linked to autosomal recessive forms of PD [4][5][6].…”

“…Deletion and point mutations of DJ-1 have been shown to be responsible for onset of familial Parkinson's disease, PARK7 [5]. DJ-1 is a multi-functional protein and plays roles in transcriptional regulation [8][9][10][11][12][13][14][15] and in modulation of signaling cascades [16][17][18][19][20] through protein-protein interaction, leading to anti-oxidative stress function [21][22][23].…”

The PTEN regulator DJ‐1 is associated with hTERT expression in clear cell renal cell carcinoma

“…5,6 Further, DJ-1 mRNA expression levels seemed to be associated with survival in lung cancer 3 and elevated levels of circulating DJ-1 and anti-DJ-1 auto-antibodies were detected in breast cancer patients 6 Recently, DJ-1 has also been identified as a gene associated with autosomal early-onset Parkinson's disease. 7 Telomerase is a ribonucleoprotein reverse transcriptase, with a catalytic subunit human telomerase reverse transcriptase (hTERT) and an integral template RNA (hTR) that dictates the synthesis of new T 2 AG 3 -repeats at the telomeres. [8][9][10][11][12] Data have indicated a correlation between the expression of hTERT mRNA and telomerase activity level during cellular differentiation, neoplastic transformation and in various malignancies including RCC.…”