ReviewTrumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes
Introduction
Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting more than 4 million people worldwide (Calabrese et al., 2007). Clinical manifestations of PD include bradykinesia, postural instability, resting tremor, and rigidity as well as increased susceptibility to memory impairment and behavioral alterations (Savitt et al., 2006). Pathologically, the disease is characterized by the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) and the presence of cytoplasmic aggregates called Lewy Bodies. Though the clinical hallmarks and macro-level pathology of PD have been extensively characterized, understanding the exact molecular basis underlying neurodegeneration remains unclear (Fig. 1, Table 1, Table 2).
Traditionally, PD has been classified as a non-genetic disease. Greater than 90% of cases are sporadic; however, rare familial forms have been identified. Autosomal recessive PD (ARPD) results from mutations in parkin, PINK1, DJ-1, ATP13A2, FBXO7, DNAJC6, SYNJ1, and PLA2G6. Studying these genes and the role they play in the disease progression has helped to elucidate common pathways in PD pathogenesis. These pathways include mitochondrial quality control, protein degradation, and oxidative stress response, all which result in dopaminergic cell death. Despite these findings, the gold standard treatment for PD patients continues to be DA replacement therapy. This therapy is symptomatically based, addressing primarily motor function, and does not alter disease progression. As a result, there is a dire need for disease-modifying therapies that halt neurodegeneration. In this review, we will discuss the genes underlying ARPD, the common pathways they are involved in, and potential strategies to therapeutically target ARPD genes and the pathways they regulate.
Mutations in parkin were first identified in Japanese families exhibiting juvenile PD (Kitada et al., 1998, Periquet, 2003). The gene was mapped to an area on chromosome 6, with deletions of exons 3–7 associated with ARPD. Further studies have identified greater than 120 various mutations including exon rearrangements, indels, and point mutations, which result in decreased parkin function. Mutations in parkin are the second most frequent form of familial PD and account for the majority of ARPD cases including both autosomal recessive juvenile PD (ARJPD) and late onset PD. In fact, nearly 50% of ARJPD cases after age 25 and up to 7% of ARJPD cases between 30 and 45 years of age carry mutations in parkin. Additionally, parkin mutations account for approximately 8.6% of early-onset PD cases (Lill, 2016). Patients with parkin mutations are typically l-DOPA responsive and maintain a slow disease course with prominent dystonia (Bonifati, 2014).
Parkin spans 1.3 Mb of DNA and is translated into a 465 amino acid E3 ubiquitin ligase with an N-terminal ubiquitin like (Ubl) domain, two RING domains, and a unique parkin domain, dubbed RING0 (Trempe and Fon, 2013). Unlike a RING-type E ligase, which catalyzes the transfer of E2-bound ubiquitin directly to its substrate, parkin uses a HECT-type E3 ligase reaction (Zhang et al., 2016). In this reaction, E2-Ub binds to parkin, whereupon a thioester bond between ubiquitin and a cysteine side chain in RING2 forms, which is then followed by ubiquitin transfer to the substrate. Parkin is capable of facilitating mono- and poly-ubiquitination to lysine 29, 48, or 63 and resides in an autoinhibited state. Parkin has been implicated in mitochondrial homeostasis, the ubiquitin-proteasome pathway, oxidative stress response, and in cell death pathways.
In 2004, scientists connected mutations in PTEN-induced putative kinase 1 (PINK1) to PD through linkage analysis of consanguineous families (Valente, 2004). The gene was mapped to chromosome 1 on the PARK6 locus. Since its initial discovery, more than 70 mutations of PINK1 have been discovered, the majority of which lead to its loss of function. Mutations in PINK1 account for approximately 3.7% of early onset cases and are the second most common cause of ARPD (Lill, 2016). Post mortem analysis of a single patient with PINK1-mediated PD reveal LB pathology, though data from this patient is currently the only data available (Bonifati, 2014). Clinically these patients exhibit a slow disease course, are responsive to l-DOPA, and have a higher reporting of psychiatric issues.
PINK1 encodes a ubiquitously expressed 581-amino acid protein with an N-terminal mitochondrial targeting sequence, a serine/threonine kinase domain, and a C-terminal regulatory domain (Trempe and Fon, 2013). Several studies have found that PINK1 localizes to both the mitochondria and the cytosol, with reports of both full length and shortened “mature” forms in each location (Lin and Kang, 2010). When localized to the mitochondria, PINK1 tethers to the outer mitochondrial membrane (OMM) with both its kinase domain and C-terminus facing the cytosol, suggesting that it acts on cytosolic substrates (Zhou et al., 2008). PINK1 is involved in mitochondrial quality control, stress pathways, and metabolism.
Mutations in DJ-1 (PARK7) were first identified in consanguineous Dutch and Italian families that displayed early onset PD (Bonifati et al., 2003). Initial studies found that mutations were caused by a large deletion in the DJ-1 coding region and by missense mutations affecting a highly conserved cysteine residue in exon 7. Since then, a variety of mutations that result in its loss of function or mislocalization. Collectively, mutations in DJ-1 account for less than 1% of familial PD cases and approximately 0.4% of early onset cases (Lill, 2016). While the pathology of DJ-1 patients is not known, patients with DJ-1 mutations have a clinical phenotype very similar to parkin- and PINK-1-mediated PD.
DJ-1 is a 24 kb gene that encodes for a ubiquitously expressed, 189-amino acid protein (Moore et al., 2006, Moore et al., 2005, Trempe and Fon, 2013). DJ-1 has been shown to function as a dimer in solution and contains an essential cysteine residue within its active site that functions as an oxidative sensor. DJ-1 has been implicated in a number of pathways including transcriptional regulation, mitochondrial quality control, and the oxidative stress response.
Mutations in ATP13A2 (PARK9) were first discovered in consanguineous families that exhibited a rare form of juvenile-onset PD known as Kufor-Rakeb syndrome (Ramirez et al., 2006). These studies found that ATP13A2 deficiencies were caused by a single nucleotide deletion, resulting in a frameshift, or a single nucleotide substitution. Further studies have found various mutations that result in ATP13A2 loss of function. The pathology in patients with ATP13A2 mutations remains unknown (Bonifati, 2014). The clinical phenotype of DJ-1 mediated PD includes pyramidal signs, poor l-DOPA response, dystonia, supranuclear palsy, and dystonia.
ATP13A2 encodes for a 5 P-Type ATPase located on lysosomal and late-endosomal membranes (van Veen et al., 2014). Studies suggest that endolysomal protein ATPase13A2 is involved in mitochondrial homeostasis, protein degradation pathways, and oxidative stress, potentially through the regulation of mono- and divalent cations, such as Zn2 + and H+ (Kett and Dauer, 2016).
Mutations in FBXO7, DNAJC6, SYNJ1, and PLA2G6 have been identified in exceedingly rare, atypical forms of juvenile ARPD (Bonifati, 2014). Due to rarity and lack of patient tissue samples, data and mechanistic details underpinning pathology caused by these mutations are limited. As a result, we will provide a brief discussion of these genes and the pathways they are implicated in; however, our review will be focused primarily on parkin, PINK1, DJ-1 and ATP13A2 pathology and therapeutically targeting said pathways.
Mutations in FBXO7 were first identified in a consanguineous Iranian family with pyramidal disease(Di Fonzo et al., 2009). These patients and others with pathogenic FBXO7 mutations exhibit pyramidal symptoms and variable l-DOPA responsiveness. FBXO7 is a member of the Skp1-Cullin-F-box-type E3 ubiquitin ligase and has been implicated in both parkin-dependent and -independent proteasome-mediated degradation and mitophagy (Zhou et al., 2016). Exome sequencing and homozygosity mapping of several consanguineous families revealed DNAJC6 and SYNJ1 as causative ARPD genes (Bonifati, 2014). (Bonifati, 2014). The clinical phenotype of DNAJC6-mediated PD includes a rapid disease course with poor response to l-DOPA, pyramidal signs, seizures, mental retardation, and dystonia (Olgiati et al., 2016). Patients with pathogenic SYNJ1 mutations also present with a rapid disease course; however, progression stabilizes in later stages of the disease. These patients have variable symptoms including seizures, cognitive impairment, and developmental issues (Drouet, 2014). DNAJC6 encodes Auxilin, a member of the Hsp40 chaperone family, while SYNJ1 encodes synaptojanin-1, a phosphoinositide phosphatase expressed in nerve terminals. These proteins are thought to work together in the recycling of synaptic vesicles, perhaps in a parkin-dependent manner. Mutations in PLA2G6 were initially associated with brain iron accumulation neurodegeneration and were later linked to ARPD. The clinical phenotype associated with PLA2G6 mutations includes good l-DOPA response, dystonia, pyramidal signs, and cognitive/psychiatric issues (Miki et al., 2017). PLA2G6 encodes the calcium-independent phospholipase A2, group VI. Recent evidence suggests that PLA2G6 deficiency is linked to aberrant ER Ca2 + signaling, leading to autophagy impairment, oxidative stress, and potentially aberration in other common ARPD-related pathways (Zhou et al., 2016).
Section snippets
Mitochondrial quality control
Numerous studies have implicated aberrant mitochondrial quality control, a highly dynamic system regulating mitochondrial health, as a primary underlying cause of neurodegeneration in PD (Pickrell and Youle, 2015, Scarffe et al., 2014). Pathways in this system include fission/fusion, mitochondrial transport, mitophagy, and mitochondrial biogenesis. Though parkin and PINK1 have been intimately linked to mitochondrial quality control, evidence suggests that DJ-1, ATP13A2, and FBXO7 may also be
Therapeutics
There are a wide variety of therapeutic strategies to target pathways regulated by ARPD genes. In this section, we will discuss strategies such as increasing parkin activity and enhancing or circumventing pathways that are abnormal in ARPD. Though this is by no means an exhaustive list, we hope to provide an overview of the most relevant potential targets that have been elucidated by understanding the function of ARPD genes and their roles in maintaining homeostasis. These targets may be
Concluding remarks
To date, there are no effective disease-modifying therapies for PD. Lack of treatment efficacy may be due to our restricted knowledge of molecular mechanisms involved, the complexity of PD pathogenesis, and perhaps the predominant use of toxin based models in drug testing. The identification of genes causing ARPD has provided etiologically based PD models and has illuminated common pathways involved in ARPD pathology, highlighting potential therapeutic targets that may halt disease progression.
Conflicts of interest
None of the authors has any conflict of interest to declare.
Acknowledgements
Supported by NIH/NINDS grant P50 NS38377 and the JPB Foundation. T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. X.B., V.L.D. and T.M.D. acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with the Johns Hopkins Hospital and the Johns Hopkins University School of Medicine and the Foundation's Parkinson's Disease Program
References (93)
- et al.
Formation of a stabilized cysteine sulfinic acid is critical for the mitochondrial function of the Parkinsonism protein DJ-1
J. Biol. Chem.
(2009) Genetics of Parkinson's disease – state of the art, 2013
Parkinsonism Relat. Disord.
(2014)- et al.
Activation of endogenous antioxidants as a common therapeutic strategy against cancer, neurodegeneration and cardiovascular diseases: a lesson learnt from DJ-1
Pharmacol. Ther.
(2015) - et al.
Pathologic and therapeutic implications for the cell biology of parkin
Mol. Cell. Neurosci.
(2015) - et al.
Mitochondria targeted therapeutic approaches in Parkinson's and Huntington's diseases
Mol. Cell. Neurosci.
(2013) - et al.
ATP13A2 regulates mitochondrial bioenergetics through macroautophagy
Neurobiol. Dis.
(2012) - et al.
DJ-1 binds to mitochondrial complex I and maintains its activity
Biochem. Biophys. Res. Commun.
(2009) - et al.
The PINK1-PARKIN mitochondrial ubiquitylation pathway drives a program of OPTN/NDP52 recruitment and TBK1 activation to promote Mitophagy
Mol. Cell
(2015) - et al.
A neo-substrate that amplifies catalytic activity of Parkinson's-disease-related kinase PINK1
Cell
(2013) - et al.
PKA phosphorylation of NCLX reverses mitochondrial calcium overload and depolarization, promoting survival of PINK1-deficient dopaminergic neurons
Cell Rep.
(2015)