COMMENTARY
COMMENTARY
Toward neuroprotective treatments of Parkinson’s disease Kwang-Soo Kima,b,1
Parkinson’s disease (PD) is, after Alzheimer’s disease, the second most-common neurodegenerative disorder affecting 1–2% of the global population over the age of 65 (1, 2). Aging being a primary risk factor for PD (3), its economic burden on our society in terms of medical care will escalate with our aging population. The major pathophysiological features of PD include selective and progressive degeneration of A9 midbrain dopaminergic (mDA) neurons in the substantia nigra and widespread accumulation of intraneuronal proteinaceous inclusions, called Lewy bodies, whose major component is misfolded α-synuclein. A9 DA neurons project to the dorsal striatum and form the nigrostriatal pathway, which controls voluntary movements. Degeneration of this pathway in PD patients results in decreased dopamine levels in the striatum, leading to clinical manifestations, such as resting tremor, rigidity, bradykinesia, and gait dysfunctions (1, 2). Since its introduction in the 1960s, dopamine replacement therapy through levodopa (L-dopa) and DA agonist administration remain the standard treatment for PD (4). Although this pharmacological treatment dramatically improves the quality of life of numerous PD patients, its efficacy wanes over time and the need for increased dosage eventually induces severe side effects, such as dyskinesia. Although there are alternative surgical treatments, such as deep brain stimulation (5), both forms of treatment are symptomatic and cannot stop or modify the disease progression. Therefore, there is a significant unmet need for the development of novel neuroprotective and diseasemodifying therapeutics for PD. In PNAS, Spathis et al. (6) introduce a novel compound, BRF110, which is a unique Nurr1: retinoid X receptor-α (RXRα)-selective “agonist” that can prevent DA neurons’ demise and striatal DA denervation in vivo in several preclinical models of PD. Remarkably, this study shows that BRF110 is not only neuroprotective in sparing mDA neurons, but also upon a single administration led to significant symptomatic improvements following mDA lesion, prompting the authors to propose that it can be used as a monotherapeutic treatment of PD (6). Numerous scientists have joined the quest to identify potential neuroprotective treatments for PD,
A
A/B
N
C
D
DBD
E
AF-1
B
Nurr1
F C
LBD
AF-2 Nurr1 Nurr1
Nurr1 RXRα BRF110
NBRE
NurRE
C NBRE:
DR5
D 5’-AAAGGTCA-3’
NurRE: 5’-TGACCTTT-n6-AAAGGTCA-3’ DR5:
5’-GGTTCACCGAAAGGTCA-3’
Fig. 1. Summary of Nurr1’s structural organization and transcriptional functions. (A) Like other nuclear receptors, Nurr1 shares several functional domains (A–F), which include DBD and LBD. (B and C ) Nurr1 activates transcription of many DA-related genes as monomers at NBRE sites, as dimers at NurRE sites, and as heterodimers with RXR at DR5 sites. (D) Nurr1 can function as transcriptional activator and repressor depending on the cellular context.
identifying and validating novel therapeutic targets and agents, including specific growth factors (e.g., GDNF), antioxidants, kinase inhibitors, and antiinflammatory agents, to name a few (reviewed in refs. 2 and 7). For example, progress in our understanding of the transcriptional regulatory mechanisms underlying the development and maintenance of mDA neurons (8) led to the identification of several key transcription factors as potential novel drug targets. In particular, two major pathways (i.e., Shh-FoxA2 and Wnt1Lmx1a) have been identified to be critical for mDA neurons’ development and maintenance and both pathways merge to activate the expression of Nurr1 (9), emphasizing Nurr1’s unique functions. Indeed, multiple lines of evidence indicate that Nurr1 is a promising drug target for PD (reviewed in refs.
a
Molecular Neurobiology Laboratory, Program in Neuroscience, Harvard Medical School, Boston, MA 02115; and bDepartment of Psychiatry, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478 Author contributions: K.-S.K. wrote the paper. Conflict of interest statement: K.-S.K. is a cofounder of NurrON Pharmaceuticals. See companion article on page 3999. 1 Email: [email protected].
www.pnas.org/cgi/doi/10.1073/pnas.1703362114
PNAS | April 11, 2017 | vol. 114 | no. 15 | 3795–3797
10–12). For example, Nurr1 is not only essential for development (13), but also for maintenance of mDA neurons in the adult brain (14). In addition, Nurr1 regulates expression of genes involved in DA function [e.g., tyrosine hydroxylase (TH), aromatic amino acid decarboxylase (AADC), and dopamine transporter (DAT)], in mDA neuron survival (e.g., GDNF receptor c-Ret genes and brain-derived neurotrophic factor), and in mitochondrial function (10). Furthermore, Nurr1 was shown to repress neurotoxic proinflammatory genes and protect mDA neurons from inflammation-related death (Fig. 1D) (15). Nurr1 is an orphan nuclear receptor belonging to the NR4A subfamily sharing a modular structure that includes a variable N-terminal region (A/B), a highly conserved central DNA-binding domain (DBD; region C), a variable linker region D, and a conserved E/F region containing the ligand-binding domain (LBD) (Fig. 1A). While the N-terminal region contains the ligand-independent activation function-1 (AF-1) transactivation domain, the C-terminal region of the LBD contains the AF-2 transactivation domain. Nurr1 is known to activate the transcription of target genes through binding to specific DNA sequences, called the NGFI-B response element (NBRE; 5′-AAAGGTCA-3′) as a monomer, or to a reverted repeat of the octanucleotide separated by a 6 nucleotide, called the Nur response element (NurRE; 5′-TGACCTTT-n6-AAAGGTCA-3′), as a homodimer (16) (Fig. 1 B and C). Also, Nurr1 can form a heterodimer with the RXR and activate target genes through binding to another sequence motif, the DR5 site, composed of a direct repeat of the core AGGTCA motif (16) (Fig. 1 B and C). Remarkably, an X-ray crystallography study revealed that Nurr1’s LBD lacks a classic ligand-binding pocket and adopts a canonical protein-fold similar to that of an agonist-bound, transcriptionally active NR LBDs (17), strongly suggesting that it is constitutively active and ligand-independent. Based on these findings, a potential approach to enhance Nurr1’s function in PD is to activate Nurr1:RXRα heterodimers using RXR ligands. Indeed, a recent study by McFarland et al. (18) demonstrated that a synthetic RXR ligand, bexarotene (a cancer drug under the name Targretin), successfully activated Nurr1’s function by inducing expression of DA-specific genes, rescued mDA neurons, and reversed behavioral deficits in 6-hydroxydopamine (6-OHDA)–lesioned rats. It is important to note that in that study, bexarotene’s effective concentration was 100-fold lower than that used in rodent cancer models (18). Another study by Volakakis et al. recently showed that bexarotene could induce expression of a subset of Nurr1 target genes, including the GDNF receptor kinase Ret (19). However, unlike the McFarland et al. study (18), bexarotene failed to protect 6-OHDA–lesioned rats (19), highlighting the importance of developing more potent Nurr1:RXR heterodimer ligands. Thus, Spathis et al. (6) attempted to develop novel and specific Nurr1:RXRα activators by synthesizing a series of compounds optimized using in silico docking simulations, and testing their effectiveness using a variety of assays. Based on this systematic structure–activity relationship analysis, Spathis et al. (6) identified BRF110, a synthetic ligand, which complements the hydrophobic L-shaped binding pocket of RXRα and activates Nurr1:RXRα heterodimers with an EC50 of ∼900 nM. Multiple lines of evidence showed that BRF110 is a promising lead compound as a PD neuroprotective treatment. First, the most salient feature of BRF110 is that it specifically activates Nurr1:RXRα, but not Nurr1: RXRγ, in a Nurr1-dependent manner. Moreover, it did not activate other heterodimers, such as VDR:RXRα, PPARγ:RXRα, RXRα:RXRα, and RXRα:RXRγ, although it modestly activated RXRα:Nur77. It will be of great interest to understand how BRF110 does not even activate an RXRα homodimer because it will provide valuable insights into its specificity. Second, using several in vitro models, such as
3796 | www.pnas.org/cgi/doi/10.1073/pnas.1703362114
SHSY-5Y cells, rat cortical neurons, and human iPS-derived DA neurons, BRF110 was found to enhance expression of DA neuronspecific genes (e.g., TH, AADC, FoxA2, and Lmx1) and to facilitate survival against MPP+ and LRR2-G2019S mutation, strongly supporting its in vitro potential of neuroprotection. Third, Spathis et al. (6) extensively address whether BRF110 can provide neuroprotection in vivo using preclinical C57BL/6 mouse models. The authors found that BRF110 intraperitoneal injection (10 mg/kg) twice a day for 6 and 14 d, starting 12 h before toxin administration in acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)lesioned mice and unilateral 6-OHDA–lesioned mice, respectively, resulted in prominent protection of mDA neurons and behavioral recovery. Interestingly, BRF110’s neuroprotective effects against MPTP toxicity was similarly observed in 129sv wild-type mice, but not in Nurr1+/− 129sv mice, indicating that proper Nurr1 expression levels are needed for its neuroprotective effects. In addition, using
The Spathis et al. study strongly suggests that BRF110 represents a promising new class of RXR ligands, offering both neuroprotective and symptomatic effects via selective activation of Nurr1:RXRα heterodimer in a Nurr1-dependent manner. adeno-associated viruses overexpressing wild-type α-synuclein, the authors further show that BRF110 could significantly rescue mDA neurons as well as striatal denervation. Last but not least, Spathis et al. (6) show that a single BRF110 (10 mg/kg) intraperitoneal injection increased TH gene expression and striatal DA and DA metabolites in wild-type mice, as well as in α-synuclein transgenic mice. Strikingly, the authors also found that the same single dose of BRF110, 8-d postacute MPTP injection or 5–6 wk postunilateral 6-OHDA injection, significantly ameliorated behavioral deficits without inducing any signs of dyskinesias for a period of 8 h postadministration. Although the Spathis et al. (6) study provides strong evidence that activation of Nurr1:RXRα is an efficient strategy to protect mDA neurons, it does not preclude the development of direct Nurr1 activation approaches. Indeed, many researchers from academia and industry attempted to identify Nurr1 activators with some success (reviewed in refs. 11 and 12). In particular, we recently identified three compounds from a Food and Drug Administration-approved drug library: that is, two antimalarial drugs, amodiaquine (AQ) and chloroquine (CQ), and a painrelieving drug (glafenine), which all share the 4-amino-7chloroquinoline scaffold, strongly supporting a structure–activity relationship (20). These compounds appear to directly bind to Nurr1’s LBD, as determined by surface plasmon resonance assays, fluorescence-quenching analysis, radioligand-binding assay using [3H]-CQ, and NMR. Notably, AQ and CQ enhanced Nurr1’s contrasting functions stimulating expression of mDAspecific proteins (e.g., TH expression), repression of microglial activation, and neurotoxic cytokine gene expression, resulting in significant neuroprotective effects in a 6-OHDA–lesioned rat model of PD without any sign of dyskinesia-like side effects (20). Thus, it will be of great interest to address whether small molecules that directly activate Nurr1 and Nurr1:RXRα can exhibit a synergistic effect for neuroprotection of mDA neurons.
Kim
In summary, the Spathis et al. (6) study strongly suggests that BRF110 represents a promising new class of RXR ligands, offering both neuroprotective and symptomatic effects via selective activation of Nurr1:RXRα heterodimer in a Nurr1-dependent manner. Thus, if its safety and efficacy are confirmed in preclinical models (such as a MPTP-lesioned monkey model) and eventually in human clinical trials, it will pave the way for the development of novel neuroprotective and disease-modifying treatments for
PD. In addition, it would be interesting to determine if Nurr1:RXRα, like Nurr1, can repress the expression of neurotoxic proinflammatory genes and whether BRF110 influences this antiinflammatory function.
Acknowledgments The author’s research is supported by the National Institute of Health (NS084869 and NS070577).
1 Dauer W, Przedborski S (2003) Parkinson’s disease: Mechanisms and models. Neuron 39:889–909. 2 Meissner WG, et al. (2011) Priorities in Parkinson’s disease research. Nat Rev Drug Discov 10:377–393. 3 Collier TJ, Kanaan NM, Kordower JH (2011) Ageing as a primary risk factor for Parkinson’s disease: Evidence from studies of non-human primates. Nat Rev Neurosci 12:359–366. 4 Cotzias GC, Papavasiliou PS, Gellene R (1969) Modification of Parkinsonism—Chronic treatment with L-dopa. N Engl J Med 280:337–345. 5 Okun MS (2012) Deep-brain stimulation for Parkinson’s disease. N Engl J Med 367:1529–1538. 6 Spathis AD, et al. (2017) Nurr1:RXRα heterodimer activation as monotherapy for Parkinson’s disease. Proc Natl Acad Sci USA 114:3999–4004. 7 Sarkar S, Raymick J, Imam S (2016) Neuroprotective and therapeutic strategies against Parkinson’s disease: Recent perspectives. Int J Mol Sci 17:E904. 8 Arenas E, Denham M, Villaescusa JC (2015) How to make a midbrain dopaminergic neuron. Development 142:1918–1936. 9 Chung S, et al. (2009) Wnt1-lmx1a forms a novel autoregulatory loop and controls midbrain dopaminergic differentiation synergistically with the SHHFoxA2 pathway. Cell Stem Cell 5:646–658. 10 Decressac M, Volakakis N, Björklund A, Perlmann T (2013) NURR1 in Parkinson disease—From pathogenesis to therapeutic potential. Nat Rev Neurol 9:629–636. 11 Dong J, Li S, Mo JL, Cai HB, Le WD (2016) Nurr1-based therapies for Parkinson’s disease. CNS Neurosci Ther 22:351–359. 12 Kim CH, Leblanc P, Kim KS (2016) 4-amino-7-chloroquinoline derivatives for treating Parkinson’s disease: Implications for drug discovery. Expert Opin Drug Discov 11:337–341. 13 Zetterström RH, et al. (1997) Dopamine neuron agenesis in Nurr1-deficient mice. Science 276:248–250. 14 Kadkhodaei B, et al. (2009) Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. J Neurosci 29:15923–15932. 15 Saijo K, et al. (2009) A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137:47–59. 16 Maira M, Martens C, Philips A, Drouin J (1999) Heterodimerization between members of the Nur subfamily of orphan nuclear receptors as a novel mechanism for gene activation. Mol Cell Biol 19:7549–7557. 17 Wang Z, et al. (2003) Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature 423:555–560. 18 McFarland K, et al. (2013) Low dose bexarotene treatment rescues dopamine neurons and restores behavioral function in models of Parkinson’s disease. ACS Chem Neurosci 4:1430–1438. 19 Volakakis N, et al. (2015) Nurr1 and retinoid X receptor ligands stimulate Ret signaling in dopamine neurons and can alleviate α-synuclein disrupted gene expression. J Neurosci 35:14370–14385. 20 Kim CH, et al. (2015) Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson’s disease. Proc Natl Acad Sci USA 112:8756–8761.
Kim
PNAS | April 11, 2017 | vol. 114 | no. 15 | 3797
COMMENTARY
Toward neuroprotective treatments of Parkinson’s disease Kwang-Soo Kima,b,1
Parkinson’s disease (PD) is, after Alzheimer’s disease, the second most-common neurodegenerative disorder affecting 1–2% of the global population over the age of 65 (1, 2). Aging being a primary risk factor for PD (3), its economic burden on our society in terms of medical care will escalate with our aging population. The major pathophysiological features of PD include selective and progressive degeneration of A9 midbrain dopaminergic (mDA) neurons in the substantia nigra and widespread accumulation of intraneuronal proteinaceous inclusions, called Lewy bodies, whose major component is misfolded α-synuclein. A9 DA neurons project to the dorsal striatum and form the nigrostriatal pathway, which controls voluntary movements. Degeneration of this pathway in PD patients results in decreased dopamine levels in the striatum, leading to clinical manifestations, such as resting tremor, rigidity, bradykinesia, and gait dysfunctions (1, 2). Since its introduction in the 1960s, dopamine replacement therapy through levodopa (L-dopa) and DA agonist administration remain the standard treatment for PD (4). Although this pharmacological treatment dramatically improves the quality of life of numerous PD patients, its efficacy wanes over time and the need for increased dosage eventually induces severe side effects, such as dyskinesia. Although there are alternative surgical treatments, such as deep brain stimulation (5), both forms of treatment are symptomatic and cannot stop or modify the disease progression. Therefore, there is a significant unmet need for the development of novel neuroprotective and diseasemodifying therapeutics for PD. In PNAS, Spathis et al. (6) introduce a novel compound, BRF110, which is a unique Nurr1: retinoid X receptor-α (RXRα)-selective “agonist” that can prevent DA neurons’ demise and striatal DA denervation in vivo in several preclinical models of PD. Remarkably, this study shows that BRF110 is not only neuroprotective in sparing mDA neurons, but also upon a single administration led to significant symptomatic improvements following mDA lesion, prompting the authors to propose that it can be used as a monotherapeutic treatment of PD (6). Numerous scientists have joined the quest to identify potential neuroprotective treatments for PD,
A
A/B
N
C
D
DBD
E
AF-1
B
Nurr1
F C
LBD
AF-2 Nurr1 Nurr1
Nurr1 RXRα BRF110
NBRE
NurRE
C NBRE:
DR5
D 5’-AAAGGTCA-3’
NurRE: 5’-TGACCTTT-n6-AAAGGTCA-3’ DR5:
5’-GGTTCACCGAAAGGTCA-3’
Fig. 1. Summary of Nurr1’s structural organization and transcriptional functions. (A) Like other nuclear receptors, Nurr1 shares several functional domains (A–F), which include DBD and LBD. (B and C ) Nurr1 activates transcription of many DA-related genes as monomers at NBRE sites, as dimers at NurRE sites, and as heterodimers with RXR at DR5 sites. (D) Nurr1 can function as transcriptional activator and repressor depending on the cellular context.
identifying and validating novel therapeutic targets and agents, including specific growth factors (e.g., GDNF), antioxidants, kinase inhibitors, and antiinflammatory agents, to name a few (reviewed in refs. 2 and 7). For example, progress in our understanding of the transcriptional regulatory mechanisms underlying the development and maintenance of mDA neurons (8) led to the identification of several key transcription factors as potential novel drug targets. In particular, two major pathways (i.e., Shh-FoxA2 and Wnt1Lmx1a) have been identified to be critical for mDA neurons’ development and maintenance and both pathways merge to activate the expression of Nurr1 (9), emphasizing Nurr1’s unique functions. Indeed, multiple lines of evidence indicate that Nurr1 is a promising drug target for PD (reviewed in refs.
a
Molecular Neurobiology Laboratory, Program in Neuroscience, Harvard Medical School, Boston, MA 02115; and bDepartment of Psychiatry, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478 Author contributions: K.-S.K. wrote the paper. Conflict of interest statement: K.-S.K. is a cofounder of NurrON Pharmaceuticals. See companion article on page 3999. 1 Email: [email protected].
www.pnas.org/cgi/doi/10.1073/pnas.1703362114
PNAS | April 11, 2017 | vol. 114 | no. 15 | 3795–3797
10–12). For example, Nurr1 is not only essential for development (13), but also for maintenance of mDA neurons in the adult brain (14). In addition, Nurr1 regulates expression of genes involved in DA function [e.g., tyrosine hydroxylase (TH), aromatic amino acid decarboxylase (AADC), and dopamine transporter (DAT)], in mDA neuron survival (e.g., GDNF receptor c-Ret genes and brain-derived neurotrophic factor), and in mitochondrial function (10). Furthermore, Nurr1 was shown to repress neurotoxic proinflammatory genes and protect mDA neurons from inflammation-related death (Fig. 1D) (15). Nurr1 is an orphan nuclear receptor belonging to the NR4A subfamily sharing a modular structure that includes a variable N-terminal region (A/B), a highly conserved central DNA-binding domain (DBD; region C), a variable linker region D, and a conserved E/F region containing the ligand-binding domain (LBD) (Fig. 1A). While the N-terminal region contains the ligand-independent activation function-1 (AF-1) transactivation domain, the C-terminal region of the LBD contains the AF-2 transactivation domain. Nurr1 is known to activate the transcription of target genes through binding to specific DNA sequences, called the NGFI-B response element (NBRE; 5′-AAAGGTCA-3′) as a monomer, or to a reverted repeat of the octanucleotide separated by a 6 nucleotide, called the Nur response element (NurRE; 5′-TGACCTTT-n6-AAAGGTCA-3′), as a homodimer (16) (Fig. 1 B and C). Also, Nurr1 can form a heterodimer with the RXR and activate target genes through binding to another sequence motif, the DR5 site, composed of a direct repeat of the core AGGTCA motif (16) (Fig. 1 B and C). Remarkably, an X-ray crystallography study revealed that Nurr1’s LBD lacks a classic ligand-binding pocket and adopts a canonical protein-fold similar to that of an agonist-bound, transcriptionally active NR LBDs (17), strongly suggesting that it is constitutively active and ligand-independent. Based on these findings, a potential approach to enhance Nurr1’s function in PD is to activate Nurr1:RXRα heterodimers using RXR ligands. Indeed, a recent study by McFarland et al. (18) demonstrated that a synthetic RXR ligand, bexarotene (a cancer drug under the name Targretin), successfully activated Nurr1’s function by inducing expression of DA-specific genes, rescued mDA neurons, and reversed behavioral deficits in 6-hydroxydopamine (6-OHDA)–lesioned rats. It is important to note that in that study, bexarotene’s effective concentration was 100-fold lower than that used in rodent cancer models (18). Another study by Volakakis et al. recently showed that bexarotene could induce expression of a subset of Nurr1 target genes, including the GDNF receptor kinase Ret (19). However, unlike the McFarland et al. study (18), bexarotene failed to protect 6-OHDA–lesioned rats (19), highlighting the importance of developing more potent Nurr1:RXR heterodimer ligands. Thus, Spathis et al. (6) attempted to develop novel and specific Nurr1:RXRα activators by synthesizing a series of compounds optimized using in silico docking simulations, and testing their effectiveness using a variety of assays. Based on this systematic structure–activity relationship analysis, Spathis et al. (6) identified BRF110, a synthetic ligand, which complements the hydrophobic L-shaped binding pocket of RXRα and activates Nurr1:RXRα heterodimers with an EC50 of ∼900 nM. Multiple lines of evidence showed that BRF110 is a promising lead compound as a PD neuroprotective treatment. First, the most salient feature of BRF110 is that it specifically activates Nurr1:RXRα, but not Nurr1: RXRγ, in a Nurr1-dependent manner. Moreover, it did not activate other heterodimers, such as VDR:RXRα, PPARγ:RXRα, RXRα:RXRα, and RXRα:RXRγ, although it modestly activated RXRα:Nur77. It will be of great interest to understand how BRF110 does not even activate an RXRα homodimer because it will provide valuable insights into its specificity. Second, using several in vitro models, such as
3796 | www.pnas.org/cgi/doi/10.1073/pnas.1703362114
SHSY-5Y cells, rat cortical neurons, and human iPS-derived DA neurons, BRF110 was found to enhance expression of DA neuronspecific genes (e.g., TH, AADC, FoxA2, and Lmx1) and to facilitate survival against MPP+ and LRR2-G2019S mutation, strongly supporting its in vitro potential of neuroprotection. Third, Spathis et al. (6) extensively address whether BRF110 can provide neuroprotection in vivo using preclinical C57BL/6 mouse models. The authors found that BRF110 intraperitoneal injection (10 mg/kg) twice a day for 6 and 14 d, starting 12 h before toxin administration in acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)lesioned mice and unilateral 6-OHDA–lesioned mice, respectively, resulted in prominent protection of mDA neurons and behavioral recovery. Interestingly, BRF110’s neuroprotective effects against MPTP toxicity was similarly observed in 129sv wild-type mice, but not in Nurr1+/− 129sv mice, indicating that proper Nurr1 expression levels are needed for its neuroprotective effects. In addition, using
The Spathis et al. study strongly suggests that BRF110 represents a promising new class of RXR ligands, offering both neuroprotective and symptomatic effects via selective activation of Nurr1:RXRα heterodimer in a Nurr1-dependent manner. adeno-associated viruses overexpressing wild-type α-synuclein, the authors further show that BRF110 could significantly rescue mDA neurons as well as striatal denervation. Last but not least, Spathis et al. (6) show that a single BRF110 (10 mg/kg) intraperitoneal injection increased TH gene expression and striatal DA and DA metabolites in wild-type mice, as well as in α-synuclein transgenic mice. Strikingly, the authors also found that the same single dose of BRF110, 8-d postacute MPTP injection or 5–6 wk postunilateral 6-OHDA injection, significantly ameliorated behavioral deficits without inducing any signs of dyskinesias for a period of 8 h postadministration. Although the Spathis et al. (6) study provides strong evidence that activation of Nurr1:RXRα is an efficient strategy to protect mDA neurons, it does not preclude the development of direct Nurr1 activation approaches. Indeed, many researchers from academia and industry attempted to identify Nurr1 activators with some success (reviewed in refs. 11 and 12). In particular, we recently identified three compounds from a Food and Drug Administration-approved drug library: that is, two antimalarial drugs, amodiaquine (AQ) and chloroquine (CQ), and a painrelieving drug (glafenine), which all share the 4-amino-7chloroquinoline scaffold, strongly supporting a structure–activity relationship (20). These compounds appear to directly bind to Nurr1’s LBD, as determined by surface plasmon resonance assays, fluorescence-quenching analysis, radioligand-binding assay using [3H]-CQ, and NMR. Notably, AQ and CQ enhanced Nurr1’s contrasting functions stimulating expression of mDAspecific proteins (e.g., TH expression), repression of microglial activation, and neurotoxic cytokine gene expression, resulting in significant neuroprotective effects in a 6-OHDA–lesioned rat model of PD without any sign of dyskinesia-like side effects (20). Thus, it will be of great interest to address whether small molecules that directly activate Nurr1 and Nurr1:RXRα can exhibit a synergistic effect for neuroprotection of mDA neurons.
Kim
In summary, the Spathis et al. (6) study strongly suggests that BRF110 represents a promising new class of RXR ligands, offering both neuroprotective and symptomatic effects via selective activation of Nurr1:RXRα heterodimer in a Nurr1-dependent manner. Thus, if its safety and efficacy are confirmed in preclinical models (such as a MPTP-lesioned monkey model) and eventually in human clinical trials, it will pave the way for the development of novel neuroprotective and disease-modifying treatments for
PD. In addition, it would be interesting to determine if Nurr1:RXRα, like Nurr1, can repress the expression of neurotoxic proinflammatory genes and whether BRF110 influences this antiinflammatory function.
Acknowledgments The author’s research is supported by the National Institute of Health (NS084869 and NS070577).
1 Dauer W, Przedborski S (2003) Parkinson’s disease: Mechanisms and models. Neuron 39:889–909. 2 Meissner WG, et al. (2011) Priorities in Parkinson’s disease research. Nat Rev Drug Discov 10:377–393. 3 Collier TJ, Kanaan NM, Kordower JH (2011) Ageing as a primary risk factor for Parkinson’s disease: Evidence from studies of non-human primates. Nat Rev Neurosci 12:359–366. 4 Cotzias GC, Papavasiliou PS, Gellene R (1969) Modification of Parkinsonism—Chronic treatment with L-dopa. N Engl J Med 280:337–345. 5 Okun MS (2012) Deep-brain stimulation for Parkinson’s disease. N Engl J Med 367:1529–1538. 6 Spathis AD, et al. (2017) Nurr1:RXRα heterodimer activation as monotherapy for Parkinson’s disease. Proc Natl Acad Sci USA 114:3999–4004. 7 Sarkar S, Raymick J, Imam S (2016) Neuroprotective and therapeutic strategies against Parkinson’s disease: Recent perspectives. Int J Mol Sci 17:E904. 8 Arenas E, Denham M, Villaescusa JC (2015) How to make a midbrain dopaminergic neuron. Development 142:1918–1936. 9 Chung S, et al. (2009) Wnt1-lmx1a forms a novel autoregulatory loop and controls midbrain dopaminergic differentiation synergistically with the SHHFoxA2 pathway. Cell Stem Cell 5:646–658. 10 Decressac M, Volakakis N, Björklund A, Perlmann T (2013) NURR1 in Parkinson disease—From pathogenesis to therapeutic potential. Nat Rev Neurol 9:629–636. 11 Dong J, Li S, Mo JL, Cai HB, Le WD (2016) Nurr1-based therapies for Parkinson’s disease. CNS Neurosci Ther 22:351–359. 12 Kim CH, Leblanc P, Kim KS (2016) 4-amino-7-chloroquinoline derivatives for treating Parkinson’s disease: Implications for drug discovery. Expert Opin Drug Discov 11:337–341. 13 Zetterström RH, et al. (1997) Dopamine neuron agenesis in Nurr1-deficient mice. Science 276:248–250. 14 Kadkhodaei B, et al. (2009) Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. J Neurosci 29:15923–15932. 15 Saijo K, et al. (2009) A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137:47–59. 16 Maira M, Martens C, Philips A, Drouin J (1999) Heterodimerization between members of the Nur subfamily of orphan nuclear receptors as a novel mechanism for gene activation. Mol Cell Biol 19:7549–7557. 17 Wang Z, et al. (2003) Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature 423:555–560. 18 McFarland K, et al. (2013) Low dose bexarotene treatment rescues dopamine neurons and restores behavioral function in models of Parkinson’s disease. ACS Chem Neurosci 4:1430–1438. 19 Volakakis N, et al. (2015) Nurr1 and retinoid X receptor ligands stimulate Ret signaling in dopamine neurons and can alleviate α-synuclein disrupted gene expression. J Neurosci 35:14370–14385. 20 Kim CH, et al. (2015) Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson’s disease. Proc Natl Acad Sci USA 112:8756–8761.
Kim
PNAS | April 11, 2017 | vol. 114 | no. 15 | 3797
