Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice

Abstract

We herein provide a thorough description of new transgenic mouse models for dentatorubral–pallidoluysian atrophy (DRPLA) harboring a single copy of the full-length human mutant DRPLA gene with 76 and 129 CAG repeats. The Q129 mouse line was unexpectedly obtained by en masse expansion based on the somatic instability of 76 CAG repeats in vivo. The mRNA expression levels of both Q76 and Q129 transgenes were each 80% of that of the endogenous mouse gene, whereas only the Q129 mice exhibited devastating progressive neurological phenotypes similar to those of juvenile-onset DRPLA patients. Electrophysiological studies of the Q129 mice demonstrated age-dependent and region-specific presynaptic dysfunction in the globus pallidus and cerebellum. Progressive shrinkage of distal dendrites of Purkinje cells and decreased currents through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and γ-aminobutyrate type A receptors in CA1 neurons were also observed. Neuropathological studies of the Q129 mice revealed progressive brain atrophy, but no obvious neuronal loss, associated with massive neuronal intranuclear accumulation (NIA) of mutant proteins with expanded polyglutamine stretches starting on postnatal day 4, whereas NIA in the Q76 mice appeared later with regional specificity to the vulnerable regions of DRPLA. Expression profile analyses demonstrated age-dependent down-regulation of genes, including those relevant to synaptic functions and CREB-dependent genes. These results suggest that neuronal dysfunction without neuronal death is the essential pathophysiologic process and that the age-dependent NIA is associated with nuclear dysfunction including transcriptional dysregulations. Thus, our Q129 mice should be highly valuable for investigating the mechanisms of disease pathogenesis and therapeutic interventions.

Neurodegeneration by polyglutamine Atrophin is not rescued by induction of autophagy

“…Also, lysotracker staining indicates correct acidification of autophagolysosomes. In fact, expression of all forms of Atro elicits massive accumulation of large acidic compartments, positive for lysotracker staining both in adult ommatidia and in imaginal discs (Figure 6a 35 S radioactivity signal incorporated in the acid-insoluble proteins after a 24-h chase with respect to 5 h of chase. BG3 neuronal cells were co-transfected with either a control pUAST plasmid or with pUAST-Atro75QN together with pMT-Gal4.…”

“…30,34 We have generated new animal models for DRPLA in D. melanogaster. The DRPLA mouse models generated in the past 35,36 have been shown to recapitulate much of the human pathology but they are less flexible and genetically amenable than Drosophila, which has proved to be a valuable tool for dissecting the polyQ pathology. 8 Our new fly models will allow faster analysis of several aspects of DRPLA neurodegeneration, also allowing detailed comparison with other polyQ disease models.…”

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

“…Purkinje neurons act as the principal output of the cerebellar cortex, and they receive 2 major types of modulatory synaptic input: climbing fibers and parallel fibers. In the mouse model of DRPLA at 12 weeks of age, a time point when there was already marked Purkinje neuron dendritic atrophy but no cell death, there is a reduction in pairedpulse ratio at both the climbing fiber-to-Purkinje neuron synapse and the parallel fiber-to-Purkinje neuron synapse [17]. The reduction in the paired-pulse ratios at both the climbing fiber and parallel fiber synapses suggests that glutamate Fig.…”

“…Studies of these models have yielded a surprising insight: the onset of apparent symptomatic impairment often precedes detectable neuropathology [10][11][12][13][14][15][16][17]. These results suggest that the cell loss observed in patient samples is representative of more advanced disease, and that reduced participation in an affected network due to neuronal loss may not be the only contributor to symptoms observed in patients.…”

The Neurogenomics View of Neurological Diseases

“…1 Over the past 3 decades, we have witnessed remarkable progress in the identification of the genes that cause hereditary neurological diseases (Figure 1). [2][3][4] This has been accomplished mainly on the basisoftheresearchparadigmknownas"positional cloning," 5,6 which uses linkage studies to pinpoint the position of genes on chromosomes followed by the identification of thecausativegene.Theidentificationofcausative genes has further made it possible to develop disease models for hereditary neurological diseases [7][8][9][10] and to develop therapeutic strategies. 11 The majority of neurological diseases, however, are sporadic without any obvious familial occurrence.…”