The C-terminal domain of LRRK2 with the G2019S mutation is sufficient to produce neurodegeneration of dopaminergic neurons in vivo.

The G2019S substitution in the kinase domain of LRRK2 (LRRK2) is the most prevalent mutation associated with Parkinson's disease (PD). Neurotoxic effects of LRRK2 are thought to result from an increase in its kinase activity as compared to wild type LRRK2. However, it is unclear whether the kinase domain of LRRK2 is sufficient to trigger degeneration or if the full length protein is required.

Potentiating tangle formation reduces acute toxicity of soluble tau species in the rat.

Tauopathies are neurodegenerative diseases characterized by the aggregation of tau protein. These pathologies exhibit a wide variety of clinical and anatomo-pathological presentations, which may result from different pathological mechanisms. Although tau inclusions are a common feature in all these diseases, recent evidence instead implicates small oligomeric aggregates as drivers of tau-induced toxicity.

Advanced imaging of transplant survival, fate, differentiation, and integration.

Stem cell-based therapy trials for the treatment of neurodegenerative diseases such as Parkinson's and Huntington's disease are being actively prepared both at the preclinical and clinical level. Preclinical validation of these stem cell transplantations necessitates to implement a translational continuum to take one pluripotent stem cell through the point of "first-in-man" clinical trial. Main steps along this translational continuum include stem cell GMP production, in vitro optimization of differentiation protocols necessary to direct stem cells to the desired neuronal phenotype, and evaluation of functional efficacy in animal models including large animal models.

Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson's disease.

Considerable progress has been made in generating fully functional and transplantable dopamine neurons from human embryonic stem cells (hESCs). Before these cells can be used for cell replacement therapy in Parkinson's disease (PD), it is important to verify their functional properties and efficacy in animal models. Here we provide a comprehensive preclinical assessment of hESC-derived midbrain dopamine neurons in a rat model of PD.

A role of mitochondrial complex II defects in genetic models of Huntington's disease expressing N-terminal fragments of mutant huntingtin.

Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of a CAG repeat encoding a polyglutamine tract in the huntingtin (Htt) protein. The mutation leads to neuronal death through mechanisms which are still unknown. One hypothesis is that mitochondrial defects may play a key role.

Normal aging modulates the neurotoxicity of mutant huntingtin.

Aging likely plays a role in neurodegenerative disorders. In Huntington's disease (HD), a disorder caused by an abnormal expansion of a polyglutamine tract in the protein huntingtin (Htt), the role of aging is unclear. For a given tract length, the probability of disease onset increases with age.

IGF-1 signaling reduces neuro-inflammatory response and sensitivity of neurons to MPTP.

Reduced expression of IGF-1R increases lifespan and resistance to oxidative stress in the mouse, raising the possibility that this also confers relative protection against the pro-parkinsonian neurotoxin MPTP, known to involve an oxidative stress component. We used heterozygous IGF-1R(+/-) mice and challenged them with MPTP. Interestingly, MPTP induced more severe lesions of dopaminergic neurons of the substantia nigra, in IGF-1R(+/-) mice than in wild-type animals.

Dopamine determines the vulnerability of striatal neurons to the N-terminal fragment of mutant huntingtin through the regulation of mitochondrial complex II.

In neurodegenerative disorders associated with primary or secondary mitochondrial defects such as Huntington's disease (HD), cells of the striatum are particularly vulnerable to cell death, although the mechanisms by which this cell death is induced are unclear. Dopamine, found in high concentrations in the striatum, may play a role in striatal cell death. We show that in primary striatal cultures, dopamine increases the toxicity of an N-terminal fragment of mutated huntingtin (Htt-171-82Q).

Quantitative gene expression profiling of mouse brain regions reveals differential transcripts conserved in human and affected in disease models.

Using serial analysis of gene expression, we collected quantitative transcriptome data in 11 regions of the adult wild-type mouse brain: the orbital, prelimbic, cingulate, motor, somatosensory, and entorhinal cortices, the caudate-putamen, the nucleus accumbens, the thalamus, the substantia nigra, and the ventral tegmental area. With >1.2 million cDNA tags sequenced, this database is a powerful resource to explore brain functions and disorders.

In vivo models of multiple system atrophy.

Multiple system atrophy (MSA) is a sporadic adult-onset neurodegenerative disorder of unknown etiology clinically characterized by a combination of parkinsonian, pyramidal, and cerebellar signs. Levodopa-unresponsive parkinsonism is present in 80% of MSA cases, and this dominant clinical presentation (MSA-P) is associated with a combined degeneration of the substantia nigra pars compacta and the striatum in anatomically related areas. The limited knowledge of the pathophysiology of MSA and the lack of therapeutic strategies prompted the development of lesion models reproducing striatonigral degeneration, the substrate of levodopa-unresponsive parkinsonism in MSA-P.

Failure of neuronal protection by inhibition of glial activation in a rat model of striatonigral degeneration.

Previous studies in rodent models of neurodegenerative disorders have demonstrated that minocycline exerts neuroprotective effects unrelated to its antimicrobial action. The purpose of the present study was to analyze whether minocycline exhibits neuroprotective activity in a rat model of striatonigral degeneration (SND), the core pathology underlying levodopa-unresponsive parkinsonism associated with multiple system atrophy (MSA). We observed no significant effect of minocycline on locomotor impairment in double-lesioned SND rats.

Rise and fall of minocycline in neuroprotection: need to promote publication of negative results.

Initial studies conducted on the neuroprotective effects of minocycline, a second-generation tetracycline, in experimental models of neurodegeneration gave promising results. However, more recently, minocycline has clearly been shown to have variable and even contradictory (beneficial or detrimental) effects in different species and models of neurological disorders, and its "neuroprotective" mechanisms remain to be clarified. Although its anti-inflammatory properties are likely to contribute to its neuroprotective effects observed in several animal models, a body of recent evidence indicates that our community should proceed with caution in the clinical use of minocycline for central nervous system disorders.

Deleterious effects of minocycline in animal models of Parkinson's disease and Huntington's disease.

Minocycline has been shown to exert anti-inflammatory effects underlying its putative neuroprotective properties in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease and in the R6/2 mouse model of Huntington's disease (HD). However, contradictory results have recently been reported. We report deleterious effects of minocycline in two phenotypic (toxic) models of Parkinson's disease and HD in monkey and mouse.

Experimental basis for the putative role of GluR6/kainate glutamate receptor subunit in Huntington's disease natural history.

Age of onset of Huntington's disease (HD) statistically correlates with the length of expanded CAG repeats in the IT15 gene. However, other factors such as polymorphism in the 3' untranslated region of the GluR6 kainate receptor gene subunit may contribute to variability in the age at onset. To investigate this issue, we studied the motor disorder and related striatal damage induced by 3-nitropropionic acid (3-NP) subacute administration in GluR6 knockout mice (GluR6(-/-)) as compared to wild-type mice.

Dopamine transporter knock-out mice are hypersensitive to 3-nitropropionic acid-induced striatal damage.

Evidence suggests that dopamine is involved in the modulation of striatal excitotoxic processes. To further investigate this issue, we studied the effects of systemic 'low-dose' (total dose, 340 mg/kg in 7 days) 3-nitropropionic acid (3-NP) intoxication in dopamine transporter knock-out mice (DAT-/-) compared to wildtype (DAT+/+) mice. Systemic 'low-dose' 3-NP induced a significant impairment in a rotarod task only in DAT-/- mice.

A simple method to measure stride length as an index of nigrostriatal dysfunction in mice.

Reduced stride length characterizes Parkinsonian gait. We aimed to demonstrate that it could be measured simply and reliably in mice by pawprints and used as an index of basal ganglia dysfunction. In C57BL/6 mice, stride length measurements proved to be consistent across measurements and experimenters.