Related Experiment Video
Updated: Jul 6, 2026
Murine Model for Parkinson's Disease: from 6-OH Dopamine Lesion to Behavioral Test
Published on: January 15, 2010
Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease
Sandro Alves1, Etienne Régulier, Isabel Nascimento-Ferreira
1Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal.
Abstract:
Machado-Joseph disease (MJD) is a fatal, dominant neurodegenerative disorder. MJD results from polyglutamine repeat expansion in the MJD-1 gene, conferring a toxic gain of function to the ataxin-3 protein. In this study, we aimed at overexpressing ataxin-3 in the rat brain using lentiviral vectors (LV), to generate an in vivo MJD genetic model and, to study the disorder in defined brain regions: substantia nigra, an area affected in MJD, cortex and striatum, regions not previously reported to be affected in MJD. LV encoding mutant or wild-type human ataxin-3 was injected in the brain of adult rats and the animals were tested for behavioral deficits and neuropathological abnormalities. Striatal pathology was confirmed in transgenic mice and human tissue. In substantia nigra, unilateral overexpression of mutant ataxin-3 led to: apomorphine-induced turning behavior; formation of ubiquitinated ataxin-3 aggregates; alpha-synuclein immunoreactivity; and loss of dopaminergic markers (TH and VMAT2). No neuropathological changes were observed upon wild-type ataxin-3 overexpression. Mutant ataxin-3 expression in striatum and cortex, resulted in accumulation of misfolded ataxin-3, and within striatum, loss of neuronal markers. Striatal pathology was confirmed by observation in MJD transgenic mice of ataxin-3 aggregates and substantial reduction of DARPP-32 immunoreactivity and, in human striata, by ataxin-3 inclusions, immunoreactive for ubiquitin and alpha-synuclein. This study demonstrates the use of LV encoding mutant ataxin-3 to produce a model of MJD and brings evidence of striatal pathology, suggesting that this region may contribute to dystonia and chorea observed in some MJD patients and may represent a target for therapies.
Insights
Researchers created a Machado-Joseph disease (MJD) rat model using lentiviral vectors to overexpress mutant ataxin-3. This study reveals new evidence of striatal pathology in MJD, potentially explaining patient symptoms and offering therapeutic targets.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Machado-Joseph disease (MJD) is a fatal, dominant neurodegenerative disorder caused by polyglutamine repeat expansion in the MJD-1 gene.
- This expansion leads to a toxic gain of function in the ataxin-3 protein, driving disease pathology.
Purpose of the Study:
- To develop an in vivo genetic model of MJD by overexpressing ataxin-3 in the rat brain using lentiviral vectors (LV).
- To investigate MJD pathology in the substantia nigra, cortex, and striatum, including regions not previously associated with the disorder.
Main Methods:
- Adult rats received stereotactic injections of LV encoding either mutant or wild-type human ataxin-3.
- Animals were assessed for behavioral deficits and neuropathological abnormalities.
- Striatal pathology was further validated in MJD transgenic mice and human tissue samples.
Main Results:
- Overexpression of mutant ataxin-3 in the substantia nigra induced apomorphine-induced turning behavior, aggregate formation, alpha-synuclein immunoreactivity, and loss of dopaminergic markers.
- No neuropathological changes were observed with wild-type ataxin-3 overexpression.
- Mutant ataxin-3 expression in the striatum and cortex led to misfolded ataxin-3 accumulation, with neuronal marker loss observed in the striatum.
Conclusions:
- Lentiviral vectors encoding mutant ataxin-3 effectively model MJD.
- The study provides evidence for striatal pathology in MJD, suggesting its contribution to dystonia and chorea.
- The striatum emerges as a potential therapeutic target for Machado-Joseph disease.
