Review Article
Involvement and interplay of Parkin, PINK1, and DJ1 in neurodegenerative and neuroinflammatory disorders

https://doi.org/10.1016/j.freeradbiomed.2012.05.040Get rights and content

Abstract

The involvement of parkin, PINK1, and DJ1 in mitochondrial dysfunction, oxidative injury, and impaired functioning of the ubiquitin-proteasome system (UPS) has been intensively investigated in light of Parkinson’s disease (PD) pathogenesis. However, these pathological mechanisms are not restricted to PD, but are common denominators of various neurodegenerative and neuroinflammatory disorders. It is therefore conceivable that parkin, PINK1, and DJ1 are also linked to the pathogenesis of other neurological diseases, including Alzheimer’s disease (AD) and multiple sclerosis (MS). The importance of these proteins in mechanisms underlying neurodegeneration is reflected by the neuroprotective properties of parkin, DJ1, and PINK1 in counteracting oxidative stress and improvement of mitochondrial and UPS functioning. This review provides a concise overview on the cellular functions of the E3 ubiquitin ligase parkin, the mitochondrial kinase PINK1, and the cytoprotective protein DJ1 and their involvement and interplay in processes underlying neurodegeneration in common neurological disorders.

Introduction

The identification of genes associated with autosomal recessive Parkinson's disease (PD), including parkin, PTEN-induced putative kinase 1 (PINK1), and DJ1, has led to more insight into the pathogenesis underlying this neurodegenerative disorder. Although mutations in genes coding for parkin, PINK1, and DJ1 are rare, they provide important insights into the biological functions of these proteins. Recent findings showed that parkin and PINK1 as well as DJ1 play a cardinal role in maintaining mitochondrial function and are reported to possess neuroprotective properties by limiting oxidative damage. Moreover they are involved in the functioning of the ubiquitin-proteasome system (UPS), which reduces accumulation of toxic protein substrates. Together, these findings demonstrate the importance of mitochondrial dysfunction, associated oxidative stress, and altered functioning of the UPS in familial and sporadic forms of PD. Importantly, it is now widely accepted that impairments of these mechanisms are common denominators of neurological disorders in general, in particular Alzheimer’s disease (AD) and multiple sclerosis (MS), and may occur already in early stages of the diseases [1], [2], [3], [4], [5].

Mitochondrial dysfunction, oxidative stress, and impaired UPS functioning are common denominators of neurological disorders

PD is a chronic and progressive disease characterized by a preferential loss of dopaminergic neurons in the substantia nigra and the presence of alpha-synuclein-positive Lewy bodies and Lewy neurites throughout the brain [6]. Evidence is emerging that apart from decreased functioning of the UPS [7] impaired mitochondrial metabolism and concomitant oxidative stress contribute to PD pathogenesis [8]. For instance, alpha-synuclein protofibrils are known to inhibit UPS functioning [9], and alpha-synuclein transgenic mice show defective proteasome activity [10]. Furthermore, neuropathological analysis of PD brain samples demonstrated extensive oxidative damage to essential macromolecules and mitochondrial proteins [11]. Moreover, experimental animal studies showed that specific mitochondrial toxins are able to induce a parkinsonian phenotype, suggesting that mitochondrial defects contribute to the pathogenesis of PD [12]. Genetic analysis of patients with inherited forms of PD has led to the discovery of mutations in genes involved in mitochondrial function or with antioxidant properties, including parkin, PINK1, and DJ-1.

AD is the most common form of dementia and clinically characterized by progressive memory impairment and cognitive decline [13]. Histopathological analysis of AD affected brain tissue reveals the presence of widespread deposition of amyloid-β (Aβ) protein throughout the brain parenchyma (senile plaques) and in the cerebrovasculature (cerebral amyloid angiopathy) [14]. In addition, intraneuronal inclusion of hyperphosphorylated tau protein, neurofibrillary tangles (NFTs), is a characteristic hallmark of AD [15]. Data are available demonstrating that impairment of the UPS results in deposition of these abnormal protein aggregates, thereby inducing neuroinflammation, mitochondrial dysfunction, and oxidative damage, which in time leads to neurodegeneration [10], [16], [17]. Moreover a combination of Aβ-mediated microglial activation and mitochondrial dysfunction induces the production of reactive oxygen species (ROS), ultimately leading to neuronal cell death [18], [19]. Notably, oxidative damage to lipids, nucleotides, proteins, mitochondrial proteins, and mtDNA occurs even in early stages of AD, and is linked to the extent of Aβ deposition in the cortex [20], [21].

MS is a complex chronic immune-mediated disease mainly affecting young adults and is characterized by focal demyelinated lesions throughout the white matter and cortex [22]. Although its etiology is unknown and MS pathogenesis is only partly understood, recent findings point toward a central role of mitochondrial dysfunction and subsequent ROS production in both the initial and the advanced stages of the disease [3], [4], [5]. We and others demonstrated the occurrence of mitochondrial defects and extensive oxidative damage in brain tissue of MS animal models and MS patients [23], [24], [25]. Furthermore, although information on the role of the UPS in MS pathogenesis is limited, signs of altered proteasome activity have been reported [26].

Taken together, there is accumulating evidence that mitochondrial dysfunction, oxidative injury, and impaired functioning of the UPS underlie various common neurodegenerative diseases. Given the neuroprotective properties of parkin, PINK1, and DJ1 in counteracting oxidative stress and improving mitochondrial and UPS function, it is likely that these PD-associated proteins play an important role also in AD and MS (Fig. 1). Here we provide a comprehensive overview on the cellular functions of parkin, PINK1, and DJ1 and their involvement and interplay in the processes underlying neurodegeneration in common neurological disorders.

Section snippets

Parkin

The parkin gene, also known as PARK2, maps the long arm of chromosome 6 (6q25.2–q27) [27], contains 12 exons, and spans approximately 1.38 Mb [28]. The parkin protein is a 465-amino acid protein containing an N-terminal ubiquitin-like domain linked to a C-terminal RING box. The latter is divided into two RING-finger motifs and has an E3 ubiquitin ligase activity [29]. In human brain, parkin is expressed in neuronal cell bodies and glial cells in the gray matter, whereas in the white matter,

PINK1

The PINK1 gene encodes a protein called PTEN-induced putative kinase 1 (PINK1), characterized by an N-terminal mitochondrial targeting motif, a highly conserved serine-threonine kinase domain, and a C-terminal autoregulatory domain [76]. PINK1 is detected in different cell types throughout the human brain with the highest expression in the hippocampus, substantia nigra, and cerebellar Purkinje cells [77]. It has been shown that PINK1 mRNA expression is abundantly found in neurons, but not in

DJ-1

DJ-1, also known as PARK7, is a homodimer that belongs to the peptidase C56 family of proteins. It is located on chromosome 1p36.23, with a transcript length of 949 bp with 7 exons and encodes a protein consisting of 189 amino acids [28]. DJ-1 was initially identified as an oncogene and its expression was found to be enhanced in several types of cancers [115]. DJ-1 protein is ubiquitously expressed in many cell types and predominantly localizes in the cytosol, but also in the nucleus and

Conclusions and future perspectives

Until recently, the role of parkin, PINK1, and DJ1 in mitochondrial dysfunction, associated oxidative stress, and impaired functioning of the UPS has been almost exclusively studied in light of PD. However, our recent findings and that of others have demonstrated that these PD-associated proteins are also linked to the pathogenesis of other neurodegenerative diseases, in particular AD and MS. Moreover, since parkin, PINK1, and DJ1 exert a plethora of fundamental protective cellular functions

Acknowledgments

This work was supported by a grant from The Brain Foundation of the Netherlands (Number F2010(1)-06 to M.M.M. Wilhelmus) and the Dutch MS Research Foundation, The Netherlands (P. Nijland and J. van Horssen).

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      DJ-1 may be involved in the pathogenesis of PD by adjusting gene expression to oxidative stress at transcriptional and post-transcriptional levels, and cushioning cytosolic redox changes (Bonifati et al., 2003). Thus, PRKN and PINK1 as well as DJ-1 are involved in PD pathogenesis through several pathways including oxidative injury, UPS dysfunction and mitochondrial dysfunction (Wilhelmus et al., 2012). Triple deletion of Prkn, Pink1 and Dj-1 in mice resembles single gene deletion that does not cause neurodegeneration, suggesting that these three genes interact in a single pathway (Corti et al., 2011).

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    These authors contributed equally.

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