Puf3p regulates the stability of nuclear‐encoded mRNAs acting in mitochondrial biogenesis and function in
Mutations in LRRK2 are the most common genetic causes of Parkinson's disease (PD). While the enzymatic activity of LRRK2 has been linked to PD, previous work has also provided support for an important role of elevated LRRK2 protein levels, independent of enzymatic activity, in PD pathogenesis. However, the mechanisms underlying the regulation of LRRK2 protein levels remain unclear. Here, we identify a role for the purine biosynthesis pathway enzyme ATIC in the regulation of LRRK2 levels and toxicity. AICAr, the precursor of ATIC substrate, regulates LRRK2 levels in a cell‐type‐specific manner
- PAR ID:
- 10441359
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- The EMBO Journal
- Volume:
- 42
- Issue:
- 15
- ISSN:
- 0261-4189
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
Saccharomyces cerevisiae . This work identifies the phosphorylation of Pop2p, a component of the deadenylase complex, as being critical for adapting Puf3p‐mediated mRNA decay upon carbon source alterations. We demonstrate that the Puf3p–Pop2p association diminishes in mitochondria‐reliant conditions and establish Yak1p, a kinase that phosphorylates Pop2p at threonine 97, as a new player in Puf3p‐mediated regulation of mRNA decay. Yak1p deletion alters the half‐life of Puf3p target mRNAs. Our findings outline a metabolism‐driven regulatory switch, whereby, in mitochondria‐independent conditions, Puf3p recruits Pop2p and the decay machinery to bound mRNAs for rapid decay. Conversely, in mitochondria‐reliant conditions, the association of Puf3p with Yak1p increases, placing Yak1p proximal to neighboring Pop2p. Subsequent Pop2p phosphorylation reduces the Puf3p–Pop2p interaction and stabilizes Puf3p target mRNAs. -
Abstract Background Mutations in leucine-rich repeat kinase 2 (
LRRK2 ) are the most common cause of familial Parkinson’s disease (PD). These mutations elevate the LRRK2 kinase activity, making LRRK2 kinase inhibitors an attractive therapeutic. LRRK2 kinase activity has been consistently linked to specific cell signaling pathways, mostly related to organelle trafficking and homeostasis, but its relationship to PD pathogenesis has been more difficult to define.LRRK2 -PD patients consistently present with loss of dopaminergic neurons in the substantia nigra but show variable development of Lewy body or tau tangle pathology. Animal models carryingLRRK2 mutations do not develop robust PD-related phenotypes spontaneously, hampering the assessment of the efficacy of LRRK2 inhibitors against disease processes. We hypothesized that mutations inLRRK2 may not be directly related to a single disease pathway, but instead may elevate the susceptibility to multiple disease processes, depending on the disease trigger. To test this hypothesis, we have previously evaluated progression of α-synuclein and tau pathologies following injection of proteopathic seeds. We demonstrated that transgenic mice overexpressing mutant LRRK2 show alterations in the brain-wide progression of pathology, especially at older ages.Methods Here, we assess tau pathology progression in relation to long-term LRRK2 kinase inhibition. Wild-type or LRRK2G2019Sknock-in mice were injected with tau fibrils and treated with control diet or diet containing LRRK2 kinase inhibitor MLi-2 targeting the IC50 or IC90 of LRRK2 for 3–6 months. Mice were evaluated for tau pathology by brain-wide quantitative pathology in 844 brain regions and subsequent linear diffusion modeling of progression.
Results Consistent with our previous work, we found systemic alterations in the progression of tau pathology in LRRK2G2019Smice, which were most pronounced at 6 months. Importantly, LRRK2 kinase inhibition reversed these effects in LRRK2G2019Smice, but had minimal effect in wild-type mice, suggesting that LRRK2 kinase inhibition is likely to reverse specific disease processes in G2019S mutation carriers. Additional work may be necessary to determine the potential effect in non-carriers.
Conclusions This work supports a protective role of LRRK2 kinase inhibition in G2019S carriers and provides a rational workflow for systematic evaluation of brain-wide phenotypes in therapeutic development.
-
Abstract The precise regulation of stem cells in the shoot apical meristems (SAMs) involves the function of the homeodomain transcription factor (TF)‐WUSCHEL (WUS). WUS has been shown to move from the site of production‐the rib‐meristem (RM), into overlaying cells of the central zone (CZ), where it specifies stem cells and also regulates the transcription of
CLAVATA3 (CLV3) . The secreted signalling peptide CLV3 activates a receptor kinase signalling that restrictsWUS transcription and also regulates the nuclear gradient of WUS by offsetting nuclear export. WUS has been shown to regulate bothCLV3 levels and spatial activation, restricting its expression to a few cells in the CZ. The HAIRY MERISTEM (HAM), a GRASS‐domain class of TFs expressed in the RM, has been shown to physically interact with WUS and regulateCLV3 expression. However, the mechanisms by which this interaction regulatesCLV3 expression non‐cell autonomously remain unclear. Here, we show that HAM function is required for regulating the WUS protein stability, and theCLV3 expression responds to altered WUS protein levels inham mutants. Thus, HAM proteins non‐cell autonomously regulatesCLV3 expression. -
Summary Among many mRNA modifications, adenine methylation at the N6position (N6‐methyladenosine, m6A) is known to affect mRNA biology extensively. The influence of m6A has yet to be assessed under drought, one of the most impactful abiotic stresses.
We show that
Arabidopsis thaliana (L.) Heynh. (Arabidopsis) plants lacking mRNA ADENOSINE METHYLASE (MTA) are drought‐sensitive. Subsequently, we comprehensively assess the impacts of MTA‐dependent m6A changes during drought on mRNA abundance, stability, and translation in Arabidopsis.During drought, there is a global trend toward hypermethylation of many protein‐coding transcripts that does not occur in
mta . We also observe complex regulation of m6A at a transcript‐specific level, possibly reflecting compensation by other m6A components. Importantly, a subset of transcripts that are hypermethylated in an MTA‐dependent manner exhibited reduced turnover and translation inmta , compared with wild‐type (WT) plants, during drought. Additionally, MTA impacts transcript stability and translation independently of m6A. We also correlate drought‐associated deposition of m6A with increased translation of modulators of drought response, such asRD29A ,COR47 ,COR413 ,ALDH2B ,ERD7 , andABF4 in WT, which is impaired inmta .m6A is dynamic during drought and, alongside MTA, promotes tolerance by regulating drought‐responsive changes in transcript turnover and translation.
-
SUMMARY Plants respond to low temperatures by altering the mRNA abundance of thousands of genes contributing to numerous physiological and metabolic processes that allow them to adapt. At the post‐transcriptional level, these cold stress‐responsive transcripts undergo alternative splicing, microRNA‐mediated regulation and alternative polyadenylation, amongst others. Recently, m6A, m5C and other mRNA modifications that can affect the regulation and stability of RNA were discovered, thus revealing another layer of post‐transcriptional regulation that plays an important role in modulating gene expression. The importance of m6A in plant growth and development has been appreciated, although its significance under stress conditions is still underexplored. To assess the role of m6A modifications during cold stress responses, methylated RNA immunoprecipitation sequencing was performed in Arabidopsis seedlings esposed to low temperature stress (4°C) for 24 h. This transcriptome‐wide m6A analysis revealed large‐scale shifts in this modification in response to low temperature stress. Because m6A is known to affect transcript stability/degradation and translation, we investigated these possibilities. Interestingly, we found that cold‐enriched m6A‐containing transcripts demonstrated the largest increases in transcript abundance coupled with increased ribosome occupancy under cold stress. The significance of the m6A epitranscriptome on plant cold tolerance was further assessed using the
mta mutant in which the major m6A methyltransferase gene was mutated. Compared to the wild‐type, along with the differences inCBFs andCOR gene expression levels, themta mutant exhibited hypersensitivity to cold treatment as determined by primary root growth, biomass, and reactive oxygen species accumulation. Furthermore, and most importantly, both non‐acclimated and cold‐acclimatedmta mutant demonstrated hypersensitivity to freezing tolerance. Taken together, these findings suggest a critical role for the epitranscriptome in cold tolerance of Arabidopsis.