The Michael J. Fox Foundation for Parkinson's Research Strategy to Advance Therapeutic Development of PINK1 and Parkin.

The role of mitochondria in Parkinson's disease (PD) has been investigated since the 1980s and is gaining attention with recent advances in PD genetics research. Mutations in and PTEN-Induced Putative Kinase 1 () are well-established causes of autosomal recessive early-onset PD. Genetic and biochemical studies have revealed that PINK1 and Parkin proteins function together in the same biological pathway to govern mitochondrial quality control.

Basal and Evoked Neurotransmitter Levels in Parkin, DJ-1, PINK1 and LRRK2 Knockout Rat Striatum.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized by the loss of neurons in the substantia nigra that project to the striatum and release dopamine (DA), which is required for normal movement. Common non-motor symptoms likely involve abnormalities with other neurotransmitters, such as serotonin, norepinephrine, acetylcholine, glycine, glutamate and gamma-aminobutyric acid (GABA). As part of a broad effort to provide better PD research tools, the Michael J.

A Proposed Roadmap for Parkinson's Disease Proof of Concept Clinical Trials Investigating Compounds Targeting Alpha-Synuclein.

The convergence of human molecular genetics and Lewy pathology of Parkinson's disease (PD) have led to a robust, clinical-stage pipeline of alpha-synuclein (α-syn)-targeted therapies that have the potential to slow or stop the progression of PD and other synucleinopathies. To facilitate the development of these and earlier stage investigational molecules, the Michael J. Fox Foundation for Parkinson's Research convened a group of leaders in the field of PD research from academia and industry, the Alpha-Synuclein Clinical Path Working Group.

Large-scale phenome analysis defines a behavioral signature for Huntington's disease genotype in mice.

Rapid technological advances for the frequent monitoring of health parameters have raised the intriguing possibility that an individual's genotype could be predicted from phenotypic data alone. Here we used a machine learning approach to analyze the phenotypic effects of polymorphic mutations in a mouse model of Huntington's disease that determine disease presentation and age of onset. The resulting model correlated variation across 3,086 behavioral traits with seven different CAG-repeat lengths in the huntingtin gene (Htt).

Animal models of Huntington's disease for translation to the clinic: best practices.

Mouse models of Huntington's disease (HD) recapitulate many aspects of the human disease. These genetically modified mice are powerful tools that are used not only to examine the pathogenesis of the disease, but also to assess the efficacy of potential new treatments. Disappointingly, in the past few years we have seen the success of potential therapies in animal studies, subsequently followed by failure in clinical trials.

Cognitive deficits in transgenic and knock-in HTT mice parallel those in Huntington's disease.

Background: Huntington's disease (HD) is characterized not only by severe motor deficits but also by early cognitive dysfunction that significantly increases the burden of the disease for patients and caregivers. Considerable efforts have concentrated, therefore, on the assessment of cognitive deficits in some HD mouse models. However, many of these models that exhibit cognitive deficits also have contemporaneous serious motor deficits, confounding interpretation of cognitive decline.

Genetic deletion of transglutaminase 2 does not rescue the phenotypic deficits observed in R6/2 and zQ175 mouse models of Huntington's disease.

Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disorder caused by expansion of CAG repeats in the huntingtin gene. Tissue transglutaminase 2 (TG2), a multi-functional enzyme, was found to be increased both in HD patients and in mouse models of the disease. Furthermore, beneficial effects have been reported from the genetic ablation of TG2 in R6/2 and R6/1 mouse lines.

A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington's disease.

Protein acetylation, which is central to transcriptional control as well as other cellular processes, is disrupted in Huntington's disease (HD). Treatments that restore global acetylation levels, such as inhibiting histone deacetylases (HDACs), are effective in suppressing HD pathology in model organisms. However, agents that selectively target the disease-relevant HDACs have not been available.

Increased Body Weight of the BAC HD Transgenic Mouse Model of Huntington's Disease Accounts for Some but Not All of the Observed HD-like Motor Deficits.

The genome of the Bacterial Artificial Chromosome (BAC) transgenic mouse model of Huntington's Disease (BAC HD) contains the 170 kb human HTT locus modified by the addition of exon 1 with 97 mixed CAA-CAG repeats. BAC HD mice present robust behavioral deficits in both the open field and the accelerating rotarod tests, two standard behavioral assays of motor function. BAC HD mice, however, also typically present significantly increased body weights relative to wildtype littermate controls (WT) which potentially confounds the interpretation of any motor deficits associated directly with the effects of mutant huntingtin.

High-Throughput Automated Phenotyping of Two Genetic Mouse Models of Huntington's Disease.

Phenotyping with traditional behavioral assays constitutes a major bottleneck in the primary screening, characterization, and validation of genetic mouse models of disease, leading to downstream delays in drug discovery efforts. We present a novel and comprehensive one-stop approach to phenotyping, the PhenoCube™. This system simultaneously captures the cognitive performance, motor activity, and circadian patterns of group-housed mice by use of home-cage operant conditioning modules (IntelliCage) and custom-built computer vision software.

Regional vulnerability in Huntington's disease: fMRI-guided molecular analysis in patients and a mouse model of disease.

Although the huntingtin gene is expressed in brain throughout life, phenotypically Huntington's disease (HD) begins only in midlife and affects specific brain regions. Here, to investigate regional vulnerability in the disease, we used functional magnetic resonance imaging (fMRI) to translationally link studies in patients with a mouse model of disease. Using fMRI, we mapped cerebral blood volume (CBV) in three groups: HD patients, symptom-free carriers of the huntingtin genetic mutation, and age-matched controls.

Caspase-6 activity in a BACHD mouse modulates steady-state levels of mutant huntingtin protein but is not necessary for production of a 586 amino acid proteolytic fragment.

Huntington's disease (HD) is caused by a mutation in the huntingtin (htt) gene encoding an expansion of glutamine repeats at the N terminus of the Htt protein. Proteolysis of Htt has been identified as a critical pathological event in HD models. In particular, it has been postulated that proteolysis of Htt at the putative caspase-6 cleavage site (at amino acid Asp-586) plays a critical role in disease progression and pathogenesis.

R6/2 Huntington's disease mice develop early and progressive abnormal brain metabolism and seizures.

A hallmark feature of Huntington's disease pathology is the atrophy of brain regions including, but not limited to, the striatum. Though MRI studies have identified structural CNS changes in several Huntington's disease (HD) mouse models, the functional consequences of HD pathology during the progression of the disease have yet to be investigated using in vivo functional MRI (fMRI). To address this issue, we first established the structural and functional MRI phenotype of juvenile HD mouse model R6/2 at early and advanced stages of disease.

Effect of the rd1 mutation on motor performance in R6/2 and wild type mice.

Homozygosis for the rd1 mutation in the Pbe6b gene results in the loss of the rod beta-subunit of the cyclic GMP phosphodiesterase and, eventually, of all rod and cone photoreceptors. The R6/2 mouse line is a widely used model of Huntington's disease (HD). The original line was made available on a mixed background obtained by crossing, via ovarian transplant, female R6/2 (on a B6CBA mixed background) with male B6CBAF1/J mice.

Circadian Abnormalities in Motor Activity in a BAC Transgenic Mouse Model of Huntington's Disease.

Huntington's disease (HD) is a progressive neurodegenerative disease marked by psychiatric and motor problems. Recently, these findings have been extended to deficits in sleep and circadian function that can be observed in HD patients and in HD mouse models, with abnormal sleep patterns correlating with symptom severity in patients. Here, we studied the behavior of the BAC HD mouse model using an 24/7 automated system; the results indicate significant lengthening of the circadian period in the mutant mice.

Comprehensive behavioral testing in the R6/2 mouse model of Huntington's disease shows no benefit from CoQ10 or minocycline.

Previous studies of the effects of coenzyme Q10 and minocycline on mouse models of Huntington's disease have produced conflicting results regarding their efficacy in behavioral tests. Using our recently published best practices for husbandry and testing for mouse models of Huntington's disease, we report that neither coenzyme Q10 nor minocycline had significant beneficial effects on measures of motor function, general health (open field, rotarod, grip strength, rearing-climbing, body weight and survival) in the R6/2 mouse model. The higher doses of minocycline, on the contrary, reduced survival.

Systematic behavioral evaluation of Huntington's disease transgenic and knock-in mouse models.

Huntington's disease (HD) is one of the few neurodegenerative diseases with a known genetic cause, knowledge that has enabled the creation of animal models using genetic manipulations that aim to recapitulate HD pathology. The study of behavioral and neuropathological phenotypes of these HD models, however, has been plagued by inconsistent results across laboratories stemming from the lack of standardized husbandry and testing conditions, in addition to the intrinsic differences between the models. We have compared different HD models using standardized conditions to identify the most robust phenotypic differences, best suited for preclinical therapeutic efficacy studies.

Knock-in mouse models of Huntington's disease.

Huntington's disease is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this fatal disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin. Numerous mouse models have been generated that constitute invaluable tools to examine the pathogenesis of the disease and to develop and evaluate novel therapies.

Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington's disease with 140 CAG repeats.

Huntington's disease (HD) is caused by an abnormal expansion of CAG repeats in the gene encoding huntingtin. The development of therapies for HD requires preclinical testing of drugs in animal models that reproduce the dysfunction and regionally specific pathology observed in HD. We have developed a new knock-in mouse model of HD with a chimeric mouse/human exon 1 containing 140 CAG repeats inserted in the murine huntingtin gene.

Early motor dysfunction and striosomal distribution of huntingtin microaggregates in Huntington's disease knock-in mice.

Huntington's disease (HD) is characterized by a progressive loss of neurons in the striatum and cerebral cortex and is caused by a CAG repeat expansion in the gene encoding huntingtin. Mice with the mutation inserted into their own huntingtin gene (knock-in mice) are, genetically, the best models of the human disease. Here we show for the first time that knock-in mice with 94 CAG repeats develop a robust and early motor phenotype at 2 months of age, characterized by increased rearing at night.

Mouse models of Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. In 1993 the mutation that causes HD was identified as an unstable expansion of CAG repeats in the IT15 gene. Since then one of the most important advances in HD research has been the generation of various mouse models that enable the exploration of early pathological, molecular and cellular abnormalities produced by the mutation.