Parkinson's disease-like neuromuscular defects occur in prenyl diphosphate synthase subunit 2 (Pdss2) mutant mice
Highlights
► Pdss2 deficient mice exhibit severe neuromuscular defects as demonstrated by behavioral testing. ► Marked reduction in TH-positive cells in the substantia nigra reflects neuromuscular impairment. ► Probucol prevented kidney disease, but not neuromuscular phenotypes, in Pdss2 missense mutants.
Introduction
Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting 1% of the population above the age of 65. The characteristic pathology involves degeneration of dopaminergic neurons in the substantia nigra pars compacta and the appearance of intracytoplasmic inclusions known as Lewy bodies (Beal, 2001). The specific etiology of PD is unknown, although both genetic and environmental factors that influence this disease have been identified. Genetic forms of PD can be caused by mutations in SCNA (PARK1), which encodes alpha-synuclein, a key component of Lewy bodies; PARK2, which encodes parkin, a ubiquitin E3 ligase; PINK1 (PARK6), which encodes a serine-threonine kinase; DJ-1 (PARK7), an oxidative stress sensor; or leucine-rich repeat kinase 2 (LRRK2, PARK8), which encodes a serine-threonine kinase (Henchcliffe and Beal, 2008).
A number of animal models of PD have been developed that either involve mutations at candidate gene loci or injection of neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), or rotenone (Abeliovich et al., 2000, Betarbet et al., 2000, Bloem et al., 1990, Goldberg et al., 2003, Sauer and Oertel, 1994). While each of these models has made a significant contribution to our understanding of PD, the complexity of the disease suggests multiple levels of pathogenesis. Among the many etiologies of PD that have been proposed, one common pathogenic factor is mitochondrial dysfunction (Henchcliffe and Beal, 2008). Reduced coenzyme Q (CoQ) levels have been observed in platelets of PD patients (Beal, 2001, Shults et al., 1997), and some studies have shown that patients with PD may benefit from CoQ10 supplementation (Beal, 2003). CoQ10 supplementation has also been shown to protect against MPTP-induced damage in aged mice (Beal, 2001). CoQ is an essential co-factor that shuttles electrons between complexes I or II and complex III in the electron transport chain, and also functions as a potent antioxidant in mitochondria. An NIH-sponsored Phase 3 clinical research trial is in progress to test the effectiveness of CoQ10 in slowing the progression of Parkinson's disease (http://www.pdtrials.org/en/browse/all/1/view/238).
To further investigate how CoQ might impact a PD phenotype, we have studied two mouse models of primary CoQ deficiency. These animals have either a homozygous missense mutation in a gene encoding a CoQ biosynthetic pathway enzyme with resultant CoQ deficiency in all tissues, or a conditional knockout of the same gene that is specifically targeted to the dopaminergic neurons. This gene was initially identified as a spontaneous mutation designated kd for kidney disease (Lyon and Hulse, 1971), and was subsequently shown to encode a mitochondrial enzyme with prenyltransferase-like activity (Peng et al., 2004). It is now called prenyl diphosphate synthase subunit 2 (Pdss2), and its gene product is one of two enzymes needed for the isoprenylation of CoQ (Saiki et al., 2005). Upon targeted knockout of Pdss2 specifically in glomerular podocytes, the kidney disease phenotype of kd/kd (B6.Pdss2kd/kd) mice was recapitulated (Peng et al., 2008). This renal phenotype could be significantly mitigated when mutant B6.Pdss2kd/kd mice were supplemented from weaning throughout adulthood with CoQ10 in their drinking water (Saiki et al., 2008). In contrast, when Pdss2 was deleted specifically in hepatocytes, myeloid cells, or renal proximal tubular epithelial cells, no disease phenotype was evident (Peng et al., 2008), suggesting that differentiated cells differ significantly with regard to their susceptibility to CoQ deficiency. We therefore examined whether behavioral deficiencies that resemble PD might appear in either the Pdss2 conditional knockouts or missense mutants.
Section snippets
Mice
The B6.Pdss2kd/kd mice were derived by backcrossing the original kd mutation onto the B6 background in the course of positional cloning (Dell et al., 2000). B6;SJL-Slc6a3tm1.1(cre)Bkmn/J mice that express Cre recombinase under the control of the dopamine transporter (DAT) promoter (Backman et al., 2006) were obtained from The Jackson Laboratory (Bar Harbor, ME) and mated with B6.Pdss2loxP/loxP mice (Peng et al., 2008). The F1 hybrids were backcrossed to the B6.Pdss2loxP/loxP strain, and
Results
Alterations in motor coordination and locomotor activity were examined in B6.Pdss2kd/kd mice that expressed the missense mutation globally as well as in Pdss2loxP/loxP;Slc6a3tm1.1(cre)Bkmn knock-out (K.O.) mice that lacked this gene specifically in dopaminergic neurons. Animals were reanalyzed over time to monitor for potential neuromuscular effects, since it is known that their lethal kidney disease phenotype does not present in missense mutants before approximately 4 months of age (Peng et
Discussion
The only overt clinical disease phenotype that has been previously observed in studies of Pdss2kd/kd missense mutant mice was restricted to severe renal glomerular disease. Only one human patient with a Pdss2 defect has been reported to date, and this was a severely affected infant who had Leigh syndrome with nephropathy (Lopez et al., 2006). The patient had refractory seizures, became progressively hypotonic, had difficulties feeding because of exhaustion, and died at 8 months of age from
Role of the funding source
The funding sources played no role in determining the study design, analysis or interpretation of the data, or the content of this manuscript.
Acknowledgments
We thank Dr. M. Flint Beal for helpful discussions, and the members of the Morphology Core for Molecular Studies in Digestive and Liver Diseases for histologic preparations. This work was supported by grants from the National Institutes of Health (R01-DK55852 to D.L.G and K-08-DK073545 to M.J.F) as well as the Gisela and Dennis Alter Chair in Pediatric Neonatology, and the Joseph Strokes Jr. Investigator program (H.I.). The content is solely the responsibility of the authors, and does not
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