Back to Search
Start Over
Cerebellum-enriched protein INPP5A contributes to selective neuropathology in mouse model of spinocerebellar ataxias type 17
- Source :
- Nature Communications, Vol 11, Iss 1, Pp 1-13 (2020), Nature Communications
- Publication Year :
- 2020
- Publisher :
- Nature Portfolio, 2020.
-
Abstract
- Spinocerebellar ataxias 17 (SCA17) is caused by polyglutamine (polyQ) expansion in the TATA box-binding protein (TBP). The selective neurodegeneration in the cerebellum in SCA17 raises the question of why ubiquitously expressed polyQ proteins can cause neurodegeneration in distinct brain regions in different polyQ diseases. By expressing mutant TBP in different brain regions in adult wild-type mice via stereotaxic injection of adeno-associated virus, we found that adult cerebellar neurons are particularly vulnerable to mutant TBP. In SCA17 knock-in mice, mutant TBP inhibits SP1-mediated gene transcription to down-regulate INPP5A, a protein that is highly abundant in the cerebellum. CRISPR/Cas9-mediated deletion of Inpp5a in the cerebellum of wild-type mice leads to Purkinje cell degeneration, and Inpp5a overexpression decreases inositol 1,4,5-trisphosphate (IP3) levels and ameliorates Purkinje cell degeneration in SCA17 knock-in mice. Our findings demonstrate the important contribution of a tissue-specific protein to the polyQ protein-mediated selective neuropathology.<br />It is not yet clear how ubiquitously-expressed proteins can cause the selective degeneration of particular populations of neurons, such as in spinocerebellar ataxia type 17, SCA17, which results from a CAG trinucleotide repeat expansion in the ubiquitously expressed transcription factor TBP. Here, the authors show that mutant TBP suppresses the cerebellum-enriched transcription of Inpp5a and link altered levels of INPP5A to the selective degeneration of cerebellar neurons.
- Subjects :
- 0301 basic medicine
Cerebellum
Mutant
Purkinje cell
General Physics and Astronomy
Inositol 1,4,5-Trisphosphate
Mice
Purkinje Cells
0302 clinical medicine
Transcription (biology)
Gene Knock-In Techniques
lcsh:Science
Multidisciplinary
biology
Neurodegeneration
Inositol Polyphosphate 5-Phosphatases
3. Good health
Cell biology
medicine.anatomical_structure
Mechanisms of disease
Spinocerebellar ataxia
Protein aggregation
congenital, hereditary, and neonatal diseases and abnormalities
Sp1 Transcription Factor
Science
Down-Regulation
Mice, Transgenic
General Biochemistry, Genetics and Molecular Biology
Article
03 medical and health sciences
medicine
Animals
Humans
Spinocerebellar Ataxias
General Chemistry
medicine.disease
TATA-Box Binding Protein
Disease Models, Animal
030104 developmental biology
HEK293 Cells
nervous system
biology.protein
lcsh:Q
TATA-binding protein
Trinucleotide repeat expansion
Peptides
Trinucleotide Repeat Expansion
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 11
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....e3ee6fb8c3023287ebe6b978c6ca0a4b