Tackling neurodegenerative diseases: animal models of Alzheimer’s disease and Parkinson’s disease

Our ageing society is confronted with a dramatic increase in incidence of age-related neurodegenerative diseases; biomedical research leading to novel therapeutic strategies is crucial to address this problem. Animal models of neurodegenerative conditions are invaluable in improving our understanding of the molecular basis of pathology, potentially revealing novel targets for intervention. Here, we review transgenic animal models of Alzheimer’s and Parkinson’s disease reported in mice, zebrafish, Caenorhabditis elegans and Drosophila melanogaster. This information will enable researchers to compare different animal models targeting disease-associated molecules by genomic engineering and to facilitate the development of novel animal models for any particular study, depending on the ultimate research goals.     

Classic toxin-induced animal models of Parkinson’s disease: 6-OHDA and MPTP

Neurological disorders in humans can be modeled in animals using standardized procedures that recreate specific pathogenic events and their behavioral outcomes. The development of animal models of Parkinsons disease (PD) is important to test new neuroprotective agents and strategies. Such animal models of PD have to mimic, at least partially, a Parkinson-like pathology and should reproduce specific features of the human disease. PD is characterized by massive degeneration of dopaminergic neurons in the substantia nigra, the loss of striatal dopaminergic fibers and a dramatic reduction of the striatal dopamine levels. The formation of cytoplasmic inclusion bodies (Lewy bodies) in surviving dopaminergic neurons represents the most important neuropathological feature of PD. Furthermore, the massive striatal dopamine deficiency causes easily detectable motor deficits in PD patients, including bradykinesia, rigidity, and resting tremor, which are the cardinal symptoms of PD. Over the years, a broad variety of experimental models of PD were developed and applied in diverse species. This review focuses on the two most common classical toxin-induced PD models, the 6-hydroxy-dopamine (6-OHDA model) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Both neurotoxins selectively and rapidly destroy catecholaminergic neurons, whereas in humans the PD pathogenesis follows a progressive course over decades. This discrepancy reflects one important and principal point of weakness related to most animal models. This review discusses the most important properties of 6-OHDA and MPTP, their modes of administration, and critically examines advantages and limitations of selected animal models. The new genetic and environmental toxin models of PD (e.g. rotenone, paraquat, maneb) are discussed elsewhere in this special issue.This work was supported by grants from the Deutsche Forschungsgemeinschaft.     

Understanding the genetic and molecular pathogenesis of Friedreich’s ataxia through animal and cellular models

In 1996, a link was identified between Friedreich’s ataxia (FRDA), the most common inherited ataxia in men, and alterations in the gene encoding frataxin (FXN). Initial studies revealed that the disease is caused by a unique, most frequently biallelic, expansion of the GAA sequence in intron 1 of FXN. Since the identification of this link, there has been tremendous progress in understanding frataxin function and the mechanism of FRDA pathology, as well as in developing diagnostics and therapeutic approaches for the disease. These advances were the subject of the 4th International Friedreich’s Ataxia Conference held on 5th–7th May in the Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. More than 200 scientists gathered from all over the world to present the results of research spanning all areas of investigation into FRDA (including clinical aspects, FRDA pathogenesis, genetics and epigenetics of the disease, development of new models of FRDA, and drug discovery). This review provides an update on the understanding of frataxin function, developments of animal and cellular models of the disease, and recent advances in trying to uncover potential molecules for therapy.     

The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinson’s disease

Purinergic Signalling - After more than two decades of preclinical and clinical studies, on August 27, 2019, the US Food and Drug Administration (FDA) approved the adenosine A2A receptor antagonist...     

On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson’s Psychosis

Parkinson’s disease psychosis (PDP) is a condition that may develop in up to 60 % of Parkinson’s patients, and is a major reason for nursing home placement for those affected. There are no FDA approved drugs for PDP but low doses of atypical anti-psychotic drugs (APDs) are commonly prescribed off-label. Only low-dose clozapine has shown efficacy in randomized controlled trials, but all APDs have black box warnings related to the increased mortality and morbidity when used in elderly demented patients. Using molecular pharmacological profiling of a large collection of marketed drugs, we discovered that potent inverse agonist activity against 5-HT_2A serotonin receptors was a common feature of atypical APDs, especially the atypical APDs used to treat PDP. Since low-dose clozapine therapy selectively blocks this receptor, it was hypothesized that a highly selective 5-HT_2A receptor inverse agonist might provide good symptom control in patients suffering from PDP, with a greatly improved safety and tolerability profile. A high throughput screening and subsequent chemical lead optimization campaign to develop potent, selective 5-HT_2A receptor inverse agonists was launched, eventually resulting in the discovery of pimavanserin. Pimavanserin displays nanomolar potency as a 5-HT_2A receptor inverse agonist, selectivity for 5-HT_2A over 5-HT_2C receptors, and no meaningful activity at any other G-protein coupled receptor. It demonstrated robust activity in preclinical models of schizophrenia and PDP, and did not worsen motoric symptoms, in contrast to the APDs tested. In a Phase III clinical trial, pimavanserin showed highly significant benefits in the primary endpoint, the scale for assessment of positive symptoms-PD, a scale adapted for use in PDP. In addition, improvements in all other efficacy endpoints, including physician’s clinical global impression, caregiver burden, night-time sleep quality and daytime wakefulness, were seen. Pimavanserin demonstrated good safety and tolerability and did not worsen motoric symptoms as assessed by the unified Parkinson’s disease rating scale parts II and III. An open-label extension study has further demonstrated that pimavanserin is safe and well-tolerated with long-term use. Pimavanserin may therefore offer a viable treatment option for patients suffering from PDP.     

The Efficacy of Traditional Chinese Medical Exercise for Parkinson’s Disease: A Systematic Review and Meta-analysis

Background and Objective

Several studies assessed the efficacy of traditional Chinese medical exercise in the management of Parkinson’s disease (PD), but its role remained controversial. Therefore, the purpose of this systematic review is to evaluate the evidence on the effect of traditional Chinese medical exercise for PD.

Methods

Seven English and Chinese electronic databases, up to October 2014, were searched to identify relevant studies. The PEDro scale was employed to assess the methodological quality of eligible studies. Meta-analysis was performed by RevMan 5.1 software.

Results

Fifteen trials were included in the review. Tai Chi and Qigong were used as assisting pharmacological treatments of PD in the previous studies. Tai Chi plus medication showed greater improvements in motor function (standardized mean difference, SMD, -0.57; 95% confidence intervals, CI, -1.11 to -0.04), Berg balance scale (BBS, SMD, -1.22; 95% CI -1.65 to -0.80), and time up and go test (SMD, -1.06; 95% CI -1.44 to -0.68). Compared with other therapy plus medication, Tai Chi plus medication also showed greater gains in motor function (SMD, -0.78; 95% CI -1.46 to -0.10), BBS (SMD, -0.99; 95% CI -1.44 to -0.54), and functional reach test (SMD, -0.77; 95% CI -1.51 to -0.03). However, Tai Chi plus medication did not showed better improvements in gait or quality of life. There was not sufficient evidence to support or refute the effect of Qigong plus medication for PD.

Conclusions

In the previous studies, Tai Chi and Qigong were used as assisting pharmacological treatments of PD. The current systematic review showed positive evidence of Tai Chi plus medication for PD of mild-to-moderate severity. So Tai Chi plus medication should be recommended for PD management, especially in improving motor function and balance. Qigong plus medication also showed potential gains in the management of PD. However, more high quality studies with long follow-up are warrant to confirm the current findings.     

Mitochondrial dynamics,cell death and the pathogenesis of Parkinson’s disease

The structure and function of the mitochondrial network is regulated by mitochondrial biogenesis, fission, fusion, transport and degradation. A well-maintained balance of these processes (mitochondrial dynamics) is essential for neuronal signaling, plasticity and transmitter release. Core proteins of the mitochondrial dynamics machinery play important roles in the regulation of apoptosis, and mutations or abnormal expression of these factors are associated with inherited and age-dependent neurodegenerative disorders. In Parkinson’s disease (PD), oxidative stress and mitochondrial dysfunction underlie the development of neuropathology. The recessive Parkinsonism-linked genes PTEN-induced kinase 1 (PINK1) and Parkin maintain mitochondrial integrity by regulating diverse aspects of mitochondrial function, including membrane potential, calcium homeostasis, cristae structure, respiratory activity, and mtDNA integrity. In addition, Parkin is crucial for autophagy-dependent clearance of dysfunctional mitochondria. In the absence of PINK1 or Parkin, cells often develop fragmented mitochondria. Whereas excessive fission may cause apoptosis, coordinated induction of fission and autophagy is believed to facilitate the removal of damaged mitochondria through mitophagy, and has been observed in some types of cells. Compensatory mechanisms may also occur in mice lacking PINK1 that, in contrast to cells and Drosophila, have only mild mitochondrial dysfunction and lack dopaminergic neuron loss. A better understanding of the relationship between the specific changes in mitochondrial dynamics/turnover and cell death will be instrumental to identify potentially neuroprotective pathways steering PINK1-deficient cells towards survival. Such pathways may be manipulated in the future by specific drugs to treat PD and perhaps other neurodegenerative disorders characterized by abnormal mitochondrial function and dynamics.     

The Neurobiology of LRRK2 and its Role in the Pathogenesis of Parkinson’s Disease

Leucine-rich repeat kinase 2 (LRRK2) is a large, widely expressed protein of largely unknown function. Mutations in the gene encoding LRRK2 have been linked to multiple diseases, including a prominent association with familial and sporadic Parkinson’s disease (PD), as well as inflammatory bowel disorders such as Crohn’s disease. The LRRK2 protein possesses both kinase and GTPase signaling domains, as well as multiple protein interaction domains. Experimental studies in both cellular and in vivo models of mutant LRRK2-induced neurodegeneration have given clues to potential function(s) of LRRK2, yet much remains unknown. For example, while it is known that intact kinase and GTPase activity are required for mutant forms of the protein to trigger cell death, the specific targets of these enzymatic activities that mediate the death of neurons are not known. In this review, we discuss the evidence linking LRRK2 to various cellular/neuronal activities such as extrinsic death and inflammatory signaling, lysosomal protein degradation, the cytoskeletal system and neurite outgrowth, vesicle trafficking, mitochondrial dysfunction, as well as multiple points of interaction with several other genes linked to the pathogenesis of PD. In order for more effective therapeutic strategies to be envisioned and implemented, the mechanisms underlying LRRK2-mediated neurodegeneration need to be better characterized. Furthermore, insights into LRRK2-associated PD pathogenesis can potentially advance our understanding of the more common sporadic forms of PD.     

The cave bear’s hibernation: reconstructing the physiology and behaviour of an extinct animal

Abstract

When studying an extinct species such as the cave bear (Ursus spelaeus ROSENMÜLLER 1794), it is possible to apply a variety of molecular biology techniques such as the study of stable isotopes or mitochondrial DNA (mDNA) to infer patterns of behaviour or physiology that would otherwise remain concealed. Throughout Europe and along time, differences in the isotopic values (δ¹³C and δ¹⁵N) of cave bears arise from environmental differences and the Pleistocene climatic evolution. The climate determines the hibernation length, during which the cave bears undergo a particular physiology that can be related to an increase in δ¹⁵N during climate cooling. In order to verify whether hibernation affected the isotopic values, we compared cave bears in different ontogenetic stages. The results show that perinatal values reflect the values for mothers during hibernation, while juveniles show differences in maternal investment. A previous study in the literature based on complete mitochondrial DNA sequences of several individuals collected from closely situated caves showed that each cave housed, almost exclusively, a single lineage of haplotypes. This pattern suggests extreme fidelity to the birth site, or homing behaviour, and that cave bears formed stable maternal social groups, at least for the purpose of hibernation. Studies of this type offer unexpected data on the palaeobiology of this extinct animal.     

Mutations in PRKN and SNCA Genes Important for the Progress of Parkinson’s Disease

Although Parkinson’s disease (PD) was first described almost 200 years ago, it remains an incurable diseasewith a cause that is not fully understood. Nowadays it is known that disturbances in the structure of pathological proteinsin PD can be caused by more than environmental and genetic factors. Despite numerous debates and controversies in theliterature about the role of mutations in the SNCA and PRKN genes in the pathogenesis of PD, it is evident that thesegenes play a key role in maintaining dopamine (DA) neuronal homeostasis and that the dysfunction of this homeostasis isrelevant to both familial (FPD) and sporadic (SPD) PD with different onset. In recent years, the importance of alphasynuclein(ASN) in the process of neurodegeneration and neuroprotective function of the Parkin is becoming better understood.Moreover, there have been an increasing number of recent reports indicating the importance of the interaction betweenthese proteins and their encoding genes. Among others interactions, it is suggested that even heterozygous substitutionin the PRKN gene in the presence of the variants +2/+2 or +2/+3 of NACP-Rep1 in the SNCA promoter, may increasethe risk of PD manifestation, which is probably due to ineffective elimination of over-expressed ASN by the mutatedParkin protein. Finally, it seems that genetic testing may be an important part of diagnostics in patients with PD and mayimprove the prognostic process in the course of PD. However, only full knowledge of the mechanism of the interactionbetween the genes associated with the pathogenesis of PD is likely to help explain the currently unknown pathways of selectivedamage to dopaminergic neurons in the course of PD.     

Role of zinc and copper ions in the pathogenetic mechanisms of Alzheimer’s and Parkinson’s diseases

Disbalance of zinc (Zn²⁺) and copper (Cu²⁺) ions in the central nervous system is involved in the pathogenesis of numerous neurodegenerative disorders such as multisystem atrophy, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Wilson-Konovalov disease, Alzheimer’s disease, and Parkinson’s disease. Among these, Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most frequent age-related neurodegenerative pathologies with disorders in Zn²⁺ and Cu²⁺ homeostasis playing a pivotal role in the mechanisms of pathogenesis. In this review we generalized and systematized current literature data concerning this problem. The interactions of Zn²⁺ and Cu²⁺ with amyloid precursor protein (APP), β-amyloid (Abeta), tau-protein, metallothioneins, and GSK3β are considered, as well as the role of these interactions in the generation of free radicals in AD and PD. Analysis of the literature suggests that the main factors of AD and PD pathogenesis (oxidative stress, structural disorders and aggregation of proteins, mitochondrial dysfunction, energy deficiency) that initiate a cascade of events resulting finally in the dysfunction of neuronal networks are mediated by the disbalance of Zn²⁺ and Cu²⁺.     

Alcohol Consumption,Types of Alcohol,and Parkinson’s Disease

Background

The epidemiologic evidence on alcohol consumption and Parkinson’s disease (PD) is equivocal. We prospectively examined total alcohol consumption and consumption of specific types of alcoholic beverage in relation to future risk of PD.

Methods

The study comprised 306,895 participants (180,235 male and 126,660 female) ages 50–71 years in 1995–1996 from the NIH-AARP Diet and Health Study. Consumption of alcoholic beverages in the past 12 months was assessed in 1995–1996. Multivariate odds ratios (OR) and 95% confidence intervals (CI) were obtained from logistic regression models.

Results

A total of 1,113 PD cases diagnosed between 2000 and 2006 were included in the analysis. Total alcohol consumption was not associated with PD. However, the association differed by types of alcoholic beverages. Compared with non-beer drinkers, the multivariate ORs for beer drinkers were 0.79 (95% CI: 0.68, 0.92) for <1 drink/day, 0.73 (95% CI: 0.50, 1.07) for 1–1.99 drinks/day, and 0.86 (95% CI: 0.60, 1.21) for ≥2 drinks/day. For liquor consumption, a monotonic increase in PD risk was suggested: ORs (95% CI) were 1.06 (0.91, 1.23), 1.22 (0.94, 1.58), and 1.35 (1.02, 1.80) for <1, 1–1.99, and ≥2 drinks/day, respectively (P for trend <0.03). Additional analyses among exclusive drinkers of one specific type of alcoholic beverage supported the robustness of these findings. The results for wine consumption were less clear, although a borderline lower PD risk was observed when comparing wine drinkers of 1–1.99 drinks/day with none drinkers (OR = 0.74, 95% CI: 0.53, 1.02).

Conclusions

Our results suggest that beer and liquor consumption may have opposite associations with PD: low to moderate beer consumption with lower PD risk and greater liquor consumption with higher risk. These findings and potential underlying mechanisms warrant further investigations.     

Circadian regulation and its disorders in Parkinson’s disease patients. Part 2: Experimental models,alpha-synuclein,and melatonin

Circadian disturbances related to Parkinson’s disease are reviewed, and possible pathogenetic mechanisms are discussed. The role of dopaminergic system degeneration in the development of circadian dysfunction is emphasized. The accumulation of α-synuclein in the suprachiasmatic nucleus is considered as a possible mechanism of circadian dysfunction unrelated to dopamine deficiency. Data on the disbalance of dopamine and melatonin levels in Parkinson’s disease patients and its role in disturbances of circadian rhythms of physiological processes are analyzed.     

Sequencing and characterization of the porcine α-galactosidase A gene: towards the generation of a porcine model for Fabry disease

Fabry disease is an inherited lysosomal disorder caused by a deficiency of alpha-galactosidase A (α-gal A). The systemic accumulation of substrate, mainly globotriaosylceramide (Gb3), results in organ failure. Although Gb3 accumulation has been observed in an α-gal A-deficient mouse model, important clinical manifestations were not seen. The pursuit of effective treatment for Fabry disease through gene therapy, for example, has been hampered by the lack of a relevant large animal model to assess the efficacy and safety of novel therapies. Towards assembling the tools to generate an alternative animal model, we have sequenced and characterized the porcine ortholog of the α-gal A gene. When compared to the human α-gal A, the porcine α-gal A showed a high level of homology in the coding regions and located at chromosome Xq22. Cell lysate and supernatants from Fabry patient-derived fibroblasts transduced with a lentiviral vector (LV) carrying the porcine α-gal A cDNA (LV/porcine α-gal A), showed high levels of α-gal A activity and its enzymological stability was similar to that of human α-gal A. Uptake of secreted porcine α-gal A was observed into non-transduced cells and was partially inhibited by soluble mannose-6-phosphate. Furthermore, Gb3 accumulation was reduced in Fabry patient-derived fibroblasts transduced with the LV/porcine α-gal A. In conclusion, we elucidated and characterized the porcine α-gal A gene and enzyme. Similarity in enzymatic profile and chromosomal location between α-gal A of porcine and human origins may be of great advantage for the development of a large animal model for Fabry disease.     

A Meta-Analysis of Randomised Placebo-Controlled Treatment Trials for Depression and Anxiety in Parkinson’s Disease

Background

Psychopharmacotherapy currently constitutes the first-line treatment for depression and anxiety in Parkinson’s disease (PD) however the efficacy of antidepressant treatments in PD is unclear. Several alternative treatments have been suggested as potentially more viable alternatives including dopamine agonists, repetitive transcranial magnetic stimulation, and cognitive behavioural therapy (CBT).

Method

A meta-analysis of randomised placebo-controlled trials for depression and/or anxiety in PD was conducted to systematically examine the efficacy of current treatments for depression and anxiety in PD.

Results

Nine trials were included. There was only sufficient data to calculate a pooled effect for antidepressant therapies. The pooled effect of antidepressants for depression in PD was moderate but non-significant (d = .71, 95% CI = −1.33 to 3.08). The secondary effect of antidepressants on anxiety in PD was large but also non-significant (d = 1.13, 95% CI = −.67 to 2.94). Two single-trials of non-pharmacological treatments for depression in PD resulted in significant large effects; Omega-3 supplementation (d = .92, 95% CI = .15 to 1.69) and CBT (d = 1.57, 95% CI = 1.06 to 2.07), and warrant further exploration.

Conclusions

There remains a lack of controlled trials for both pharmacological and non-pharmacological treatments for depression and anxiety in PD which limits the conclusions which can be drawn. While the pooled effects of antidepressant therapies in PD were non-significant, the moderate to large magnitude of each pooled effect is promising. Non-pharmacological approaches show potential for depression in PD however more research is required.