A new humanized ataxin-3 knock-in mouse model combines the genetic features, pathogenesis of neurons and glia and late disease onset of SCA3/MJD

Abstract

Spinocerebellar ataxia type 3 (SCA3/MJD) is a neurodegenerative disease triggered by the expansion of CAG repeats in the ATXN3 gene. Here, we report the generation of the first humanized ataxin-3 knock-in mouse model (Ki91), which provides insights into the neuronal and glial pathology of SCA3/MJD. First, mutant ataxin-3 accumulated in cell nuclei across the Ki91 brain, showing diffused immunostaining and forming intranuclear inclusions. The humanized allele revealed expansion and contraction of CAG repeats in intergenerational transmissions. CAG mutation also exhibited age-dependent tissue-specific expansion, which was most prominent in the cerebellum, pons and testes of Ki91 animals. Moreover, Ki91 mice displayed neuroinflammatory processes, showing astrogliosis in the cerebellar white matter and the substantia nigra that paralleled the transcriptional deregulation of Serpina3n, a molecular sign of neurodegeneration and brain damage. Simultaneously, the cerebellar Purkinje cells in Ki91 mice showed neurodegeneration, a pronounced decrease in Calbindin D-28k immunoreactivity and a mild decrease in cell number, thereby modeling the degeneration of the cerebellum observed in SCA3. Moreover, these molecular and cellular neuropathologies were accompanied by late behavioral deficits in motor coordination observed in rotarod and static rod tests in heterozygous Ki91 animals. In summary, we created an ataxin-3 knock-in mouse model that combines the molecular and behavioral disease phenotypes with the genetic features of SCA3. This model will be very useful for studying the pathogenesis and responses to therapy of SCA3/MJD and other polyQ disorders.

Questions and (some) answers on reactive astrocytes

“…Among them, Serpina3n and Lcn2 were further validated as strongly, but transiently induced following LPS injection or MCAO (Zamanian et al, ). They are also induced in other disease models (Itoh et al, ; Suk, ; Switonski, Szlachcic, Krzyzosiak, & Figiel, ). Change in transcriptome is a conserved feature of astrocyte reaction, similarly observed in Drosophila glia (Lu et al, ).…”

Caffeine alleviates progressive motor deficits in a transgenic mouse model of spinocerebellar ataxia

“…Despite evidence of variable Purkinje cell degeneration in MJD patients and models, 47,48 this could lead to exacerbation of the disease in these cells compared with what is observed in human neuropathology, and therefore the observations may actually be even more relevant in the context of pure SCAs, in which the neurodegeneration occurs primarily in Purkinje cells. However, this conclusion was based on the exploration of a particular MJD mouse model with selective overexpression of mutant ataxin-3 in the cerebellum, in contrast to the more widespread expression in MJD patients.…”

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

“…Subsequently, Padmanabhan et al reported that anti‐chymotrypsin induces tau phosphorylation in neurons. In various neurological diseases, the expression of SERPINA3N in the brain has been found to be significantly upregulated . Recent studies have also shown that SERPINA3N is clearly related to many inflammation‐related diseases, such as hypothalamic inflammation, retinal neuroinflammation, allergic airway inflammation, myocarditis, and atherosclerosis .…”

“…Serpina3n encodes anti‐chymotrypsin, which is a widely expressed member of the serpin superfamily and has recently been recognized as a key component of the inflammatory response in the brain . In many neurological diseases, anti‐chymotrypsin in the brain has been found to be markedly upregulated . Serpina3n was also reported as a highly expressed gene in persistently active astrocytes .…”