Extrinsic BDNF delivery delayed onset of motor deficits and Purkinje neuron pathology in <i>ATXN1[82Q]</i> mice supporting its use as a novel therapeutic for SCA1.
Loss-of-function of fly Pak3 or Pak1, whose mammalian homologs belong to Group I of PAK proteins, reduces ATXN1 levels, and accordingly, improves disease pathology in a Drosophila model of SCA1.
We further examine the implications of PKA-mediated phosphorylation at ATXN1-S776 on SCA1 through genetic manipulation of the PKA catalytic subunit Cα in Pcp2-ATXN1[82Q] mice.
These results indicate that NF-κB signaling is required for increase in microglial numbers and TNF-α production in the cerebella of ATXN1[82Q] mouse model of SCA1.
Using RNA sequencing transcriptomics, OXPHOS complex assembly analysis and oxygen consumption assays, we report that in the presence of mutant polyglutamine-expanded ataxin-1, SCA1 mice display deficits in cerebellar OXPHOS complex I (NADH-coenzyme Q oxidoreductase).
Using RNA sequencing transcriptomics, OXPHOS complex assembly analysis and oxygen consumption assays, we report that in the presence of mutant polyglutamine-expanded ataxin-1, SCA1 mice display deficits in cerebellar OXPHOS complex I (NADH-coenzyme Q oxidoreductase).
We have examined the effect of depleting microglia during the early stage of disease by using PLX, an inhibitor of colony-stimulating factor 1 receptor (CSFR1), on disease severity in a mouse model of SCA1.
These findings indicate that HSF1 is a key molecule in the regulation of the protein homeostasis of the polyQ-expanded mutant ATXN1 and that Hsp90 has potential as a novel therapeutic target in patients with SCA1.
The underlying mechanism does not involve modulation of mitochondrial biogenesis, but dysregulation of the activity of the metabolic regulators glycogen synthase kinase 3B (GSK3β), decreased in Atxn1-KO and increased in SCA1 mice, and mechanistic target of rapamycin (serine/threonine kinase) (mTOR), unchanged in the Atxn1-KO and decreased in SCA1 mice cerebellum before the onset of ataxic symptoms.
SYNE1 was originally discovered in 2007 as the causal gene underlying autosomal recessive spinocerebellar ataxia 1, a disease clinically thought to manifest with mainly pure cerebellar ataxia.
These findings indicate that HSF1 is a key molecule in the regulation of the protein homeostasis of the polyQ-expanded mutant ATXN1 and that Hsp90 has potential as a novel therapeutic target in patients with SCA1.
Over-expression of GLaz is able to reduce p62 and ubiquitinated proteins levels when rapamycin-dependent and SCA1-dependent inductions of autophagy are combined.
Over-expression of GLaz is able to reduce p62 and ubiquitinated proteins levels when rapamycin-dependent and SCA1-dependent inductions of autophagy are combined.
Over-expression of GLaz is able to reduce p62 and ubiquitinated proteins levels when rapamycin-dependent and SCA1-dependent inductions of autophagy are combined.
Over-expression of GLaz is able to reduce p62 and ubiquitinated proteins levels when rapamycin-dependent and SCA1-dependent inductions of autophagy are combined.
Over-expression of GLaz is able to reduce p62 and ubiquitinated proteins levels when rapamycin-dependent and SCA1-dependent inductions of autophagy are combined.
Breeding Pum1(+/-) mice to SCA1 mice (Atxn1(154Q/+)) exacerbated disease progression, whereas breeding them to Atxn1(+/-) mice normalized Ataxin1 levels and largely rescued the Pum1(+/-) phenotype.
In particular, RpA1, which had the largest effect on lifespan in the SCA1 fly model, was located at the hub position linked to such core repair systems, including homologous recombination (HR).
Herein, we found a new function of ataxin-1: the modulation of Pp2a activity and the regulation of its holoenzyme composition, with the polyglutamine mutation within Atxn1 altering this function in the SCA1 mouse cerebellum before disease onset.