Proteomic profiling reveals mitochondrial dysfunction in the cerebellum of transgenic mice overexpressing DYRK1A, a Down syndrome candidate gene

Abstract

IntroductionDYRK1A is a dual-specificity kinase that is overexpressed in Down syndrome (DS) and plays a key role in neurogenesis, neuronal differentiation and function, cognitive phenotypes, and aging. Dyrk1A has also been implicated in cerebellar abnormalities observed in association with DS, and normalization of Dyrk1A dosage rescues granular and Purkinje cell densities in a trisomic DS mouse model. However, the underlying molecular mechanisms governing these processes are unknown.MethodsTo shed light on the effects of Dyrk1A overexpression in the cerebellum, here we investigated the cerebellar proteome in transgenic Dyrk1A overexpressing mice in basal conditions and after treatment with green tea extract containing epigallocatechin-3-gallate (EGCG), a DYRK1A inhibitor.Results and DiscussionOur results showed that Dyrk1A overexpression alters oxidative phosphorylation and mitochondrial function in the cerebellum of transgenic mice. These alterations are significantly rescued upon EGCG-containing green tea extract treatment, suggesting that its effects in DS could depend in part on targeting mitochondria, as shown by the partially restoration by the treatment of the increased mtDNA copy number in TG non-treated mice.

DYRK1A signalling synchronizes the mitochondrial import pathways for metabolic rewiring

“…It will also be interesting to test whether increased levels of DYRK1A might interfere with the feedback loop and thus impact on mitochondrial protein biogenesis. The discovery of the DYRK1A-TOM70 axis as regulatory hub that links the main mitochondrial protein import pathways now paves the way to reach a mechanistic understanding of the described links of Down syndrome and dysfunctional mitochondrial energy metabolism 70 , 71 .…”

Flip a coin: cell senescence at the maternal–fetal interface

“…A recent study has shown that the mouse cerebellum exhibited active oxidative phosphorylation and mitochondrial malfunction the overexpression of dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), a dual-specificity kinase that was upregulated in DS and aging. This report indicated that in DS, DYRK1A targeted mitochondria and induced cell senescence [117]. Cell senescence was observed in pregnancies complicated by PE, fetal growth restriction, preterm birth, and DS.…”