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Abstract
Parkinson’s disease (PD) is one of the major neurodegenerative disorders. Mitochondrial malfunction is implicated in PD pathogenesis. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-induced putative kinase 1 (PINK1), a serine/threonine kinase, plays an important role in the quality control of mitochondria and more than 70 PINK1 mutations have been identified to cause early-onset PD. However, the regulation of PINK1 gene expression remains elusive. In the present study, we identified the transcription start site (TSS) of the human PINK1 gene using switching mechanism at 5’end of RNA transcription (SMART RACE) assay. The TSS is located at 91 bp upstream of the translation start site ATG. The region with 104 bp was identified as the minimal promoter region by deletion analysis followed by dual luciferase assay. Four functional cis-acting nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB)-binding sites within the PINK1 promoter were identified. NFκB overexpression led to the up-regulation of PINK1 expression in both HEK293 cells and SH-SY5Y cells. Consistently, lipopolysaccharide (LPS), a strong activator of NFκB, significantly increased PINK1 expression in SH-SY5Y cells. Taken together, our results clearly suggested that PINK1 expression is tightly regulated at its transcription level and NFκB is a positive regulator for PINK1 expression.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease [1]
Our results demonstrated that PINK1 expression is tightly regulated at its transcriptional level and that NFκB is a positive regulator for PINK1 expression
Cloning the human PINK1 gene promoter and mapping its transcription initiation site The human PINK1 gene spans a region of 18,056 bp on chromosome 1p36
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease [1]. PD patients commonly suffer from muscular dysfunction which resulted in body rigidity, tremors, bradykinesia, posture instability, and Parkinsonian gait. In dysfunctional mitochondria with reduced mitochondrial membrane potential and mitochondrial oxidative stress, full-length PINK1 is aggregated on the mitochondrial membrane and recruits Parkin to mitochondria through the phosphorylation of Parkin, resulting in mitochondrial autophagy. More than 70 mutations in the PINK1 gene were identified in familial PD in an autosomal recessive manner [12,13] Most of these mutations fail to phosphorylate and recruit Parkin to mitochondria, leading to the accumulation of dysfunctional mitochondria and eventually neuronal death. This strongly suggests that PINK1 plays a critical role in PD pathogenesis and dysregulation of PINK1 may contribute to the development of PD
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