Genetic Models Of Parkinson's Disease Research Articles

Aging accelerates locomotor decline in PINK1 knockout rats in association with decreased nigral, but not striatal, dopamine and tyrosine hydroxylase expression

Parkinson's disease (PD) rodent models provide insight into the relationship between nigrostriatal dopamine (DA) signaling and locomotor function. Although toxin-based rat models produce frank nigrostriatal neuron loss and eventual motor decline characteristic of PD, the rapid nature of neuronal loss may not adequately translate premotor traits, such as cognitive decline. Unfortunately, rodent genetic PD models, like the Pink1 knockout (KO) rat, often fail to replicate the differential severity of striatal DA and tyrosine hydroxylase (TH) loss, and a bradykinetic phenotype, reminiscent of human PD. To elucidate this inconsistency, we evaluated aging as a progression factor in the timing of motor and non-motor cognitive impairments. Male PINK1 KO and age-matched wild type (WT) rats were evaluated in a longitudinal study from 3 to 16 months old in one cohort, and in a cross-sectional study of young adult (6–7 months) and aged (18–19 months) in another cohort. Young adult PINK1 KO rats exhibited hyperkinetic behavior associated with elevated DA and TH in the substantia nigra (SN), which decreased therein, but not striatum, in the aged KO rats. Additionally, norepinephrine levels decreased in aged KO rats in the prefrontal cortex (PFC), paired with a higher DA levels in young and aged KO. Although a younger age of onset characterizes familial forms of PD, our results underscore the critical need to consider age-related factors. Moreover, the results indicate that compensatory mechanisms may exist to preserve locomotor function, evidenced by increased DA in the SN early in the lifespan, in response to deficient PINK1 function, which declines with aging and the onset of motor decline.

The Impact of Intestinal Microbiota and Toll-like Receptor 2 Signaling on α-Synuclein Pathology in Nontransgenic Mice Injected with α-Synuclein Preformed Fibrils.

Intestinal microbiota and Toll-like receptor 2 (TLR2), which can bind lipoteichoic acid produced by microbiota, might contribute to the pathogenesis of Parkinson's disease (PD), which is characterized by α-synuclein accumulation. Although the contribution of intestinal microbiota and TLR2 to PD pathology was validated in genetic PD models, evidence suggests that the effects of TLR2 signaling on proteinopathy might depend on the presence of a genetic etiology. We examined the impact of intestinal microbiota and TLR2 signaling on α-synuclein pathology in a nontransgenic mouse model of sporadic PD. While an α-synuclein preformed fibrils injection successfully reproduced PD pathology by inducing accumulation of α-synuclein aggregates, microglial activation and increased TLR2 expression in the brains of nontransgenic mice, antibiotic-induced reduction in the density of intestinal microbiota and TLR2 knockout had small impact on these changes. These findings, which are in contrast to those reported in transgenic mice harboring transgene encoding α-synuclein, indicate that the contribution of intestinal microbiota and TLR2 signaling to α-synuclein pathogenesis might be influenced by the presence of a genetic etiology. Additionally, these findings suggest that integrating insights from this experimental model and genetic models would further advance our understanding of the molecular mechanisms underlying sporadic PD.

Alpha-synuclein pathology in the "weaver" mouse, a genetic model of dopaminergic denervation.

Alpha-synuclein plays a pivotal role in Parkinson's disease (PD) pathogenesis, with α-synuclein aggregates/oligomers being identified as toxic species and phosphorylation at Serine 129 promoting aggregation/oligomerization. We investigated the biochemical profile of α-synuclein in the "weaver" mouse, a genetic PD model. Our results revealed increased Serine 129 phosphorylation in the midbrain, striatum, and cortex at a phase of established dopaminergic degeneration on postnatal day 100. These results indicate α-synuclein pathology already at this stage and the potential for age-related progress. Our findings confirm that the "weaver" mouse is an invaluable genetic model to study α-synuclein pathogenesis during PD progression.

Modeling familial and sporadic Parkinson's disease in small fishes.

The establishment of animal models for Parkinson's disease (PD) has been challenging. Nevertheless, once established, they will serve as valuable tools for elucidating the causes and pathogenesis of PD, as well as for developing new strategies for its treatment. Following the recent discovery of a series of PD causative genes in familial cases, teleost fishes, including zebrafish and medaka, have often been used to establish genetic PD models because of their ease of breeding and gene manipulation, as well as the high conservation of gene orthologs. Some of the fish lines can recapitulate PD phenotypes, which are often more pronounced than those in rodent genetic models. In addition, a new experimental teleost fish, turquoise killifish, can be used as a sporadic PD model, because it spontaneously manifests age-dependent PD phenotypes. Several PD fish models have already made significant contributions to the discovery of novel PD pathological features, such as cytosolic leakage of mitochondrial DNA and pathogenic phosphorylation in α-synuclein. Therefore, utilizing various PD fish models with distinct degenerative phenotypes will be an effective strategy for identifying emerging facets of PD pathogenesis and therapeutic modalities.

Dopaminergic Input Regulates the Sensitivity of Indirect Pathway Striatal Spiny Neurons to Brain-Derived Neurotrophic Factor.

Motor dysfunction in Parkinson's disease (PD) is closely linked to the dopaminergic depletion of striatal neurons and altered synaptic plasticity at corticostriatal synapses. Dopamine receptor D1 (DRD1) stimulation is a crucial step in the formation of long-term potentiation (LTP), whereas dopamine receptor D2 (DRD2) stimulation is needed for the formation of long-term depression (LTD) in striatal spiny projection neurons (SPNs). Tropomyosin receptor kinase B (TrkB) and its ligand brain-derived neurotrophic factor (BDNF) are centrally involved in plasticity regulation at the corticostriatal synapses. DRD1 activation enhances TrkB's sensitivity for BDNF in direct pathway spiny projection neurons (dSPNs). In this study, we showed that the activation of DRD2 in cultured striatal indirect pathway spiny projection neurons (iSPNs) and cholinergic interneurons causes the retraction of TrkB from the plasma membrane. This provides an explanation for the opposing synaptic plasticity changes observed upon DRD1 or DRD2 stimulation. In addition, TrkB was found within intracellular structures in dSPNs and iSPNs from Pitx3-/- mice, a genetic model of PD with early onset dopaminergic depletion in the dorsolateral striatum (DLS). This dysregulated BDNF/TrkB signaling might contribute to the pathophysiology of direct and indirect pathway striatal projection neurons in PD.

In vivo18F-DOPA PET imaging identifies a dopaminergic deficit in a rat model with a G51D α-synuclein mutation.

Parkinson's disease (PD) is a neurodegenerative condition with several major hallmarks, including loss of substantia nigra neurons, reduction in striatal dopaminergic function, and formation of α-synuclein-rich Lewy bodies. Mutations in SNCA, encoding for α-synuclein, are a known cause of familial PD, and the G51D mutation causes a particularly aggressive form of the condition. CRISPR/Cas9 technology was used to introduce the G51D mutation into the endogenous rat SNCA gene. SNCAG51D/+ and SNCAG51D/G51D rats were born in Mendelian ratios and did not exhibit any severe behavourial defects. L-3,4-dihydroxy-6-18F-fluorophenylalanine (18F-DOPA) positron emission tomography (PET) imaging was used to investigate this novel rat model. Wild-type (WT), SNCAG51D/+ and SNCAG51D/G51D rats were characterized over the course of ageing (5, 11, and 16 months old) using 18F-DOPA PET imaging and kinetic modelling. We measured the influx rate constant (Ki) and effective distribution volume ratio (EDVR) of 18F-DOPA in the striatum relative to the cerebellum in WT, SNCAG51D/+ and SNCAG51D/G51D rats. A significant reduction in EDVR was observed in SNCAG51D/G51D rats at 16 months of age indicative of increased dopamine turnover. Furthermore, we observed a significant asymmetry in EDVR between the left and right striatum in aged SNCAG51D/G51D rats. The increased and asymmetric dopamine turnover observed in the striatum of aged SNCAG51D/G51D rats reflects one aspect of prodromal PD, and suggests the presence of compensatory mechanisms. SNCAG51D rats represent a novel genetic model of PD, and kinetic modelling of 18F-DOPA PET data has identified a highly relevant early disease phenotype.

Changes in Liver Lipidomic Profile in G2019S-LRRK2 Mouse Model of Parkinson's Disease.

The identification of Parkinson's disease (PD) biomarkers has become a main goal for the diagnosis of this neurodegenerative disorder. PD has not only been intrinsically related to neurological problems, but also to a series of alterations in peripheral metabolism. The purpose of this study was to identify metabolic changes in the liver in mouse models of PD with the scope of finding new peripheral biomarkers for PD diagnosis. To achieve this goal, we used mass spectrometry technology to determine the complete metabolomic profile of liver and striatal tissue samples from WT mice, 6-hydroxydopamine-treated mice (idiopathic model) and mice affected by the G2019S-LRRK2 mutation in LRRK2/PARK8 gene (genetic model). This analysis revealed that the metabolism of carbohydrates, nucleotides and nucleosides was similarly altered in the liver from the two PD mouse models. However, long-chain fatty acids, phosphatidylcholine and other related lipid metabolites were only altered in hepatocytes from G2019S-LRRK2 mice. In summary, these results reveal specific differences, mainly in lipid metabolism, between idiopathic and genetic PD models in peripheral tissues and open up new possibilities to better understand the etiology of this neurological disorder.

Neuroprotective potential of plant derived parenchymal stem cells extract on environmental and genetic models of Parkinson disease through attenuation of oxidative stress and neuroinflammation.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by both motor and non-motor features. The current treatment regimen for PD are dopamine enhancers which have been reported to worsen the disease prognosis after long term treatment, thus, the need for better treatment options. This study sought to investigate the protective action of Double Stem Cell® (DSC), a blend of stem cells extracts from Swiss apples (Malus Domestica) and Burgundy grapes (Vitis vinifera) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism in mice and genetic model of PD in Drosophila melanogaster. Male albino mice were pretreated with MPTP (4 × 20mg/kg, i.p., two hourly in 8h), twelve hours before administration of DSC (8, 40, or 200mg/kg, p.o.). Thereafter, behavioural, biochemical and immunohistochemical assays were carried out. The impact of vehicle or DSC supplementation on α-synuclein aggregation was evaluated in Drosophila melanogaster using the UAS-Gal4 system, female DDC-Gal4 flies were crossed with male UAS-α-synuclein, the progenies were examined for fecundity, locomotion, memory, and lifespan. MPTP-induced motor deficits in open field test (OFT), working memory impairment (Y-maze test (YMT)) and muscle incoordination (rotarod test) were ameliorated by DSC (8, 40 or 200mg/kg) through dose-dependent and significant improvements in motor, cognitive and motor coordination. Moreso, MPTP exposure caused significant increase in lipid peroxidation and decrease in antioxidant enzymes activities (glutathione, catalase and superoxide dismutase) in the midbrain which were attenuated by DSC. MPTP-induced expression of microglia (iba-1), astrocytes (glia fibrillary acidic protein; GFAP) as well as degeneration of dopamine neurons (tyrosine hydroxylase positive neurons) in the substantia nigra (SN) were reversed by DSC. Supplementation of flies feed with graded concentration of DSC (0.8, 4 or 20mg/ml) did not affect fecundity but improved climbing activity and lifespan. Findings from this study showed that Double Stem Cell improved motor and cognitive functions in both mice and Drosophila through attenuation of neurotoxin-induced oxidative stress and neuroinflammation.

UPRmt activation protects against MPP+-induced toxicity in a cell culture model of Parkinson's disease

The pathogenesis of Parkinson's disease (PD) remains elusive, but mitochondrial dysfunction is believed to be one crucial step in its pathogenesis. The mitochondrial unfolded protein response (UPRmt) is an important mitochondrial quality control strategy that maintains mitochondrial function in response to disturbances of mitochondrial protein homeostasis. Activation of the UPRmt and the beneficial effect of rescuing mitochondrial proteostasis have been reported in several genetic models of PD. However, the pathogenic relevance of the UPRmt in idiopathic PD is unknown. The present study examined the link between the UPRmt and mitochondrial dysfunction in 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells. Treatment with MPP + induced activation of the UPRmt, reflected by an increase in the expression of UPRmt-related chaperones, proteases, and transcription mediators. UPRmt activation that was induced by overexpressing mutant ornithine transcarbamylase significantly reduced the production of mitochondrial reactive oxygen species (ROS) and improved cell survival in SH-SY5Y cells following MPP+ treatment. Moreover, the overexpression of activating transcription factor 5 (mammalian UPRmt transcription factor) conferred protection against MPP+-induced ROS production and against cell death in SH-SY5Y cells. Overall, our results demonstrate the beneficial effect of UPRmt activation in MPP + -treated cells, shedding new light on the mechanism of mitochondrial dysfunction in the pathogenesis of PD.

GDNF signaling in subjects with minimal motor deficits and Parkinson's disease

The failure of glial cell derived neurotropic factor to be efficacious in blinded clinical trials for Parkinson's disease may be due to alterations in signaling receptors and downstream signaling molecules. To test this hypothesis, brain sections were obtained from older adults with no motor deficit (n = 6), minimal motor deficits (n = 10), and clinical diagnosis of Parkinson's disease (n = 10) who underwent motor examination proximate to death. Quantitative unbiased stereology and densitometry were performed to analyze RET and phosphorylated ribosomal protein S6 expression in nigral neurons. Individuals with no motor deficit had extensive and intense RET and phosphorylated ribosomal protein S6 immunoreactive neurons in substantia nigra. The number and staining intensity of RET-immunoreactive neurons were reduced moderately in subjects with minimal motor deficits and severely reduced in Parkinson's disease relative to no motor deficit group. The number and staining intensity of phosphorylated ribosomal protein S6 was more markedly reduced in both subjects with minimal motor deficits and Parkinson's disease. Reductions in levels of RET and phosphorylated ribosomal protein S6 were recapitulated in a non-human primate genetic Parkinson's disease model based on over-expression of human mutant α-synuclein (A53T). These data indicate that for neurotrophic factors to be effective in patients with minimal motor deficits or PD, these factors would likely have to upregulate RET and phosphorylated ribosomal protein S6 immunoreactive neurons in substantia nigra .

Neuroprotection by the Immunomodulatory Drug Pomalidomide in the Drosophila LRRK2WD40 Genetic Model of Parkinson's Disease.

The search for new disease-modifying drugs for Parkinson’s disease (PD) is a slow and highly expensive process, and the repurposing of drugs already approved for different medical indications is becoming a compelling alternative option for researchers. Genetic variables represent a predisposing factor to the disease and mutations in leucine-rich repeat kinase 2 (LRRK2) locus have been correlated to late-onset autosomal-dominant PD. The common fruit fly Drosophila melanogaster carrying the mutation LRRK2 loss-of-function in the WD40 domain (LRRK2WD40), is a simple in vivo model of PD and is a valid tool to first evaluate novel therapeutic approaches to the disease. Recent studies have suggested a neuroprotective activity of immunomodulatory agents in PD models. Here the immunomodulatory drug Pomalidomide (POM), a Thalidomide derivative, was examined in the Drosophila LRRK2WD40 genetic model of PD. Mutant and wild type flies received increasing POM doses (1, 0.5, 0.25 mM) through their diet from day 1 post eclosion, until postnatal day (PN) 7 or 14, when POM’s actions were evaluated by quantifying changes in climbing behavior as a measure of motor performance, the number of brain dopaminergic neurons and T-bars, mitochondria integrity. LRRK2WD40 flies displayed a spontaneous age-related impairment of climbing activity, and POM significantly and dose-dependently improved climbing performance both at PN 7 and PN 14. LRRK2WD40 fly motor disability was underpinned by a progressive loss of dopaminergic neurons in posterior clusters of the protocerebrum, which are involved in the control of locomotion, by a low number of T-bars density in the presynaptic bouton active zones. POM treatment fully rescued the cell loss in all posterior clusters at PN 7 and PN 14 and significantly increased the T-bars density. Moreover, several damaged mitochondria with dilated cristae were observed in LRRK2WD40 flies treated with vehicle but not following POM. This study demonstrates the neuroprotective activity of the immunomodulatory agent POM in a genetic model of PD. POM is an FDA-approved clinically available and well-tolerated drug used for the treatment of multiple myeloma. If further validated in mammalian models of PD, POM could rapidly be clinically tested in humans.

Dopamine regulates spine density in striatal projection neurons in a concentration-dependent manner

Dopaminergic afferents innervate spiny projection neurons (SPNs) in the striatum, maintaining basal ganglia activity. The loss of striatal innervation is the hallmark of Parkinson's disease (PD), which is characterized by dopaminergic denervation. A lack of dopamine in the dorsal striatum induces plasticity changes in SPNs. However, PD-associated denervation is progressive, and how plasticity is modified in partially innervated areas is poorly understood. The most studied models of PD are based on the use of neurotoxins that induce an almost complete striatal denervation. To investigate the impact of partial dopamine (DA) innervation in striatal plasticity, we use a genetic model of PD, Aphakia (Ak) mice, whose striatum presents an increasing dorso-ventral gradient of dopamine innervation. We studied SPNs in three different areas (dorsal, middle and ventral, with low, moderate and high innervation by tyrosine hydroxylase TH-positive axons, respectively) using fast scan cyclic voltammetry, microiontophoresis, immunohistochemistry and patch clamp techniques. Our data show an increasing dorso-ventral gradient of extracellular DA levels, overlapping with the gradient of TH innervation. Interestingly, spine loss in both direct (d-SPN) and indirect SPNs (i-SPN) decreases from dorsal to ventral in the parkinsonian striatum of Ak mice, following the decrease in DA levels. However, their dendritic trees and the number of nodes are only reduced in the poorly innervated dorsal areas and remain unaltered in moderate and highly innervated areas. The firing rate of direct SPNs does not change in either moderate or highly innervated areas, but increases in poorly innervated areas. In contrast, action potential frequency of indirect SPNs does not change along the dorso-ventral innervation gradient. Our findings indicate that spine density in d-SPNs and i-SPNs varies in a dopamine concentration-dependent manner, indicating that both d- and i-SPN are similarly innervated by DA.

Enhancing glycolysis attenuates Parkinson's disease progression in models and clinical databases.

Parkinson's disease (PD) is a common neurodegenerative disease that lacks therapies to prevent progressive neurodegeneration. Impaired energy metabolism and reduced ATP levels are common features of PD. Previous studies revealed that terazosin (TZ) enhances the activity of phosphoglycerate kinase 1 (PGK1), thereby stimulating glycolysis and increasing cellular ATP levels. Therefore, we asked whether enhancement of PGK1 activity would change the course of PD. In toxin-induced and genetic PD models in mice, rats, flies, and induced pluripotent stem cells, TZ increased brain ATP levels and slowed or prevented neuron loss. The drug increased dopamine levels and partially restored motor function. Because TZ is prescribed clinically, we also interrogated 2 distinct human databases. We found slower disease progression, decreased PD-related complications, and a reduced frequency of PD diagnoses in individuals taking TZ and related drugs. These findings suggest that enhancing PGK1 activity and increasing glycolysis may slow neurodegeneration in PD.

Chapter 24 - Animal models of olfactory dysfunction in neurodegenerative diseases

Olfactory dysfunction seems to occur earlier than classic motor and cognitive symptoms in many neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease (AD). Thus, the use of the olfactory system as a clinical marker for neurodegenerative diseases is helpful in the characterization of prodromal stages of these diseases, early diagnostic strategies, differential diagnosis, and, potentially, prediction of treatment success. The use of genetic and neurotoxin animal models has contributed to the understanding of the mechanisms underlying olfactory dysfunction in a number of neurodegenerative diseases. In this chapter, we provide an overview of behavioral and neurochemical alterations observed in animal models of different neurodegenerative diseases (such as genetic and Aβ infusion models for AD and neurotoxins and genetic models of PD), in which olfactory dysfunction has been described.

Genetically engineered animal models of Parkinson's disease: From worm to rodent.

Parkinson's disease (PD) is a progressive neurological disorder characterised by aberrant accumulation of insoluble proteins, including alpha-synuclein, and a loss of dopaminergic neurons in the substantia nigra. The extended neurodegeneration leads to a drop of striatal dopamine levels responsible for disabling motor and non-motor impairments. Although the causes of the disease remain unclear, it is well accepted among the scientific community that the disorder may also have a genetic component. For that reason, the number of genetically engineered animal models has greatly increased over the past two decades, ranging from invertebrates to more complex organisms such as mice and rats. This trend is growing as new genetic variants associated with the disease are discovered. The EU Joint Programme - Neurodegenerative Disease Research (JPND) has promoted the creation of an online database aiming at summarising the different features of experimental models of Parkinson's disease. This review discusses available genetic models of PD and the extent to which they adequately mirror the human pathology and reflects on future development and uses of genetically engineered experimental models for the study of PD.

Dopamine D2 receptor activation potently inhibits striatal glutamatergic transmission in a G2019S LRRK2 genetic model of Parkinson's disease

Among genetic abnormalities identified in Parkinson's disease (PD), mutations of the leucine-rich repeat kinase2 (LRRK2) gene, such as the G2019S missense mutation linked to enhanced kinase activity, are the most common. While the complex role of LRRK2 has not been fully elucidated, evidence that mutated kinase activity affects synaptic transmission has been reported. Thus, our aim was to explore possible early alterations of neurotransmission produced by the G2019S LRRK2 mutation in PD. We performed electrophysiological patch-clamp recordings of striatal spiny projection neurons (SPNs) in the G2019S-Lrrk2 knock-in (KI) mouse model of PD, in D1994S kinase-dead (KD), Lrrk2 knock-out (KO) and wild-type (WT) mice. In G2019S Lrrk2 KI mice, basal spontaneous glutamatergic transmission, synaptic facilitation, and NMDA/AMPA ratios were unchanged, whereas the stimulation of dopamine (DA) D2 receptor by quinpirole reduced the spontaneous and evoked excitatory postsynaptic currents (EPSC). Quinpirole reduced the EPSC amplitude of SPNs in KI but not in KD, KO and WT mice, suggesting that the enhanced LRRK2 kinase activity induced by the G2019S mutation is associated with the observed functional alteration of SPNs synaptic transmission. The effect of quinpirole was mediated by a phospholipase C (PLC)-dependent release of endocannabinoid, with subsequent activation of presynaptic cannabinoid receptor 1 and reduced release of glutamate. The key role of DA D2 receptor in reducing glutamatergic output in our LRRK2 genetic model of PD further supports the use of DA agonists in the treatment of early PD patients with LRRK2 mutations to counteract the disease progression.

Differential Synaptic Remodeling by Dopamine in Direct and Indirect Striatal Projection Neurons in Pitx3-/- Mice, a Genetic Model of Parkinson's Disease.

In toxin-based models of Parkinson's disease (PD), striatal projection neurons (SPNs) exhibit dendritic atrophy and spine loss concurrent with an increase in excitability. Chronic l-DOPA treatment that induces dyskinesia selectively restores spine density and excitability in indirect pathway SPNs (iSPNs), whereas spine loss and hyperexcitability persist in direct pathway SPNs (dSPNs). These alterations have only been characterized in toxin-based models of PD, raising the possibility that they are an artifact of exposure to the toxin, which may engage compensatory mechanisms independent of the PD-like pathology or due to the loss of dopaminergic afferents. To test all these, we studied the synaptic remodeling in Pitx3-/- or aphakia mice, a genetic model of PD, in which most of the dopamine neurons in the substantia nigra fail to fully differentiate and to innervate the striatum. We made 3D reconstructions of the dendritic arbor and measured excitability in identified SPNs located in dorsal striatum of BAC-Pitx3-/- mice treated with saline or l-DOPA. Both dSPNs and iSPNs from BAC-Pitx3-/- mice had shorter dendritic trees, lower spine density, and more action potentials than their counterparts from WT mice. Chronic l-DOPA treatment restored spine density and firing rate in iSPNs. By contrast, in dSPNs, spine loss and hyperexcitability persisted following l-DOPA treatment, which is similar to what happens in 6-OHDA WT mice. This indicates that dopamine-mediated synaptic remodeling and plasticity is independent of dopamine innervation during SPN development and that Pitx3-/- mice are a good model because they develop the same pathology described in the toxins-based models and in human postmortem studies of advanced PD.SIGNIFICANCE STATEMENT As the only genetic model of Parkinson's disease (PD) that develops dyskinesia, Pitx3-/- mice reproduce the behavioral effects seen in humans and are a good system for studying dopamine-induced synaptic remodeling. The studies we present here establish that the structural and functional synaptic plasticity that occur in striatal projection neurons in PD and in l-DOPA-induced dyskinesia are specifically due to modulation of the neurotransmitter dopamine and are not artifacts of the use of chemical toxins in PD models. In addition, our findings provide evidence that synaptic plasticity in the Pitx3-/- mouse is similar to that seen in toxin models despite its lack of dopaminergic innervation of the striatum during development. Pitx3-/- mice reproduced the alterations described in patients with advanced PD and in well accepted toxin-based models of PD and dyskinesia. These results further consolidate the fidelity of the Pitx3-/- mouse as a PD model in which to study the morphological and physiological remodeling of striatal projection neurons by administration of l-DOPA and other drugs.

Dopaminergic Neuron-Specific Autophagy-Deficient Mice.

None of the current genetic Parkinson's disease (PD) models in mouse recapitulates all features of PD. Additionally, only a few of these models develop mild dopamine (DA) neurodegeneration. And the most parsimonious explanation for the lack of DA neurodegeneration in genetic PD models is a compensatory mechanism that results from adaptive changes during development, making it hard to observe the degenerative phenotype over the life span of mice. Here, we characterize DA neuron-specific autophagy-deficient mice and provide in vivo evidence for Lewy body formation. Atg7-deficient mice demonstrate typical Lewy pathology, including endogenous synuclein and neuronal loss, which resembles PD. Furthermore DA levels are affected by dopaminergic neuronal loss. The age-related motor dysfunction and pathology in DA neurons suggest that impairment of autophagy is a potential mechanism underlying the pathology of PD.

BNN-20, a synthetic microneurotrophin, strongly protects dopaminergic neurons in the “weaver” mouse, a genetic model of dopamine-denervation, acting through the TrkB neurotrophin receptor

Neurotrophic factors are among the most promising treatments aiming at slowing or stopping and even reversing Parkinson's disease (PD). However, in most cases, they cannot readily cross the human blood-brain-barrier (BBB).Herein, we propose as a therapeutic for PD the small molecule 17-beta-spiro-[5-androsten-17,2'-oxiran]-3beta-ol (BNN-20), a synthetic analogue of DHEA, which crosses the BBB and is deprived of endocrine side-effects. Using the “weaver” mouse, a genetic model of PD, which exhibits progressive dopaminergic neurodegeneration in the Substantia Nigra (SN), we have shown that long-term administration (P1-P21) of BNN-20 almost fully protected the dopaminergic neurons and their terminals, via i) a strong anti-apoptotic effect, probably mediated through the Tropomyosin receptor kinase B (TrkB) neurotrophin receptor's PI3K-Akt-NF-κB signaling pathway, ii) by exerting an efficient antioxidant effect, iii) by inducing significant anti-inflammatory activity and iv) by restoring Brain-Derived Neurotrophic Factor (BDNF) levels. By intercrossing “weaver” with NGL mice (dual GFP/luciferase-NF-κΒ reporter mice, NF-κΒ.GFP.Luc), we obtained Weaver/NGL mice that express the NF-κB reporter in all somatic cells. Acute BNN-20 administration to Weaver/NGL mice induced a strong NF-κB-dependent transcriptional response in the brain as detected by bioluminescence imaging, which was abolished by co-administration of the TrkB inhibitor ANA-12. This indicates that BNN-20 exerts its beneficial action (at least in part) through the TrkB-PI3K-Akt-NF-κB signaling pathway.These results could be of clinical relevance, as they suggest BNN-20 as an important neuroprotective agent acting through the TrkB neurotrophin receptor pathway, mimicking the action of the endogenous neurotrophin BDNF. Thus BNN-20 could be proposed for treatment of PD.

Loss of PINK1 leads to metabolic deficits in adult neural stem cells and impedes differentiation of newborn neurons in the mouse hippocampus.

Emerging evidence suggests that mitochondrial dynamics regulates adult hippocampal neurogenesis (AHN). Although abnormal AHN has been linked to depression, anxiety, and cognitive dysfunction, which are features of neurodegenerative conditions, including Parkinson's disease (PD), the impact of mitochondrial deficits on AHN have not been explored previously in a model of neurodegeneration. Here, we used PTEN-induced kinase 1-deficient (PINK1-/- ) mice that lacked a mitochondrial kinase mutated in recessive familial PD. We show that mitochondrial defects, elevated glycolysis, and increased apoptosis are associated with impaired but not abrogated differentiation of PINK1-deficient neural stem cells (NSCs) in culture. In the dentate gyrus of PINK1-/- mice, newly generated doublecortin-positive neurons show aberrant dendritic morphology, and their maturation is compromised compared with wild-type mice. In addition, in vivo labeling of NSCs with 5-ethynyl-2'-deoxyuridine shows that proliferating NSC numbers are normal, but the differentiation of NSCs to doublecortin-positive neuroblasts and mature NeuN+ neurons is impeded in PINK1-/- mice. Finally, we demonstrate that home cage activity and corticosterone levels of PINK1-/- mice are normal, thereby excluding reduced physical activity and increased stress as causes of neurogenesis defects. Our results reveal a new and important relationship between mitochondrial dysfunction and impaired AHN in a genetic PD model. Targeting mitochondrial function and metabolism to increase AHN may hold promise for the treatment of affective disorders and the mitigation of related symptoms in PD and other neurodegenerative conditions.-Agnihotri, S. K., Shen, R., Li, J., Gao, X., Büeler, H. Loss of PINK1 leads to metabolic deficits in adult neural stem cells and impedes differentiation of newborn neurons in the mouse hippocampus.