Mitochondrial haplogroups and cognitive progression in Parkinson's disease.

Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U# had a 41% lower risk of cognitive progression with P = 2.42 × 10-6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 × 10-5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time.

Identification of diagnostic and prognostic biomarkers of PD using a multiplex proteomics approach.

Given the complexity of Parkinson's disease (PD), achieving acceptable diagnostic and prognostic accuracy will require the support of a panel of diverse biomarkers. We used Proximity extension assays to measure a panel of 92 proteins in CSF of 120 newly diagnosed PD patients and 45 control subjects without neurological disease. From 75 proteins detectable in the CSF of >90% of the subjects, regularized regression analysis identified four proteins (ß-NGF, CD38, tau and NCAN) as downregulated in newly diagnosed PD patients (age at diagnosis 67.2 ± 9.4 years) compared to controls (age 65.4 ± 10.9 years). Higher tau (ß -0.82 transformed MMSE points/year, 95% CI -1.37 to -0.27, P = 0.005) was also linked to faster cognitive decline over the first ten years after PD diagnosis. These findings provide insights into multiple aspects of PD pathophysiology and may serve as the foundation for identifying new biomarkers and therapeutic targets.

GBA and APOE Impact Cognitive Decline in Parkinson's Disease: A 10-Year Population-Based Study.

BACKGROUND: Common genetic variance in apolipoprotein E (APOE), ß-glucocerebrosidase (GBA), microtubule-associated protein tau (MAPT), and α-synuclein (SNCA) has been linked to cognitive decline in Parkinson's disease (PD), although studies have yielded mixed results. OBJECTIVES: To evaluate the effect of genetic variants in APOE, GBA, MAPT, and SNCA on cognitive decline and risk of dementia in a pooled analysis of six longitudinal, non-selective, population-based cohorts of newly diagnosed PD patients. METHODS: 1002 PD patients, followed for up to 10 years (median 7.2 years), were genotyped for at least one of APOE-ε4, GBA mutations, MAPT H1/H2, or SNCA rs356219. We evaluated the effect of genotype on the rate of cognitive decline (Mini-Mental State Examanation, MMSE) using linear mixed models and the development of dementia (diagnosed using standardized criteria) using Cox regression; multiple comparisons were accounted for using Benjamini-Hochberg corrections. RESULTS: Carriers of APOE-ε4 (n = 281, 29.7%) and GBA mutations (n = 100, 10.3%) had faster cognitive decline and were at higher risk of progression to dementia (APOE-ε4, HR 3.57, P < 0.001; GBA mutations, HR 1.76, P = 0.001) than non-carriers. The risk of cognitive decline and dementia (HR 5.19, P < 0.001) was further increased in carriers of both risk genotypes (n = 23). No significant effects were observed for MAPT or SNCA rs356219. CONCLUSIONS: GBA and APOE genotyping could improve the prediction of cognitive decline in PD, which is important to inform the clinical trial selection and potentially to enable personalized treatment © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cannabis use in Parkinson's disease-A nationwide online survey study.

OBJECTIVES: The aim of this study was to investigate the frequency of use, attitudes toward, and experiences with cannabis and cannabis-related products among people with Parkinson's disease (PwP) living in Norway. METHODS: Between February and August 2021, PwP and their caregivers were invited to participate in an anonymous online survey study on cannabis use. N = 530 PwP completed the 24-item survey collecting data on the participants' history of cannabis use, perceived benefits and adverse effects of cannabis use, and expectations toward health care professionals. N = 108 caregivers completed a brief survey detailing their experience with cannabis use. RESULTS: A total of 59 (11.3%) of PwP reported previous or current use of cannabis, compared to 7 (6.6%) of caregivers. Cannabis use was associated with increased disease duration, but not age or gender. Improvement in motor function (69.5%), sleep (52.5%), and pain (37.3%) was the most frequently perceived benefits of cannabis use, with benefits more frequently reported by current than previous users. While half (50.8%) of cannabis users had sought advice from a health care professional regarding cannabis use, only 55 (19.9%) of non-users with an interest in cannabis use had discussed the topic with health care professionals. Principal barriers for discussing cannabis use with health care professionals are discussed. CONCLUSIONS: One in 20 PwP reports cannabis use, and non-users report widespread interest in cannabis. The use of cannabis is often not reported and unknown for health care professionals, arguing for a vigilant approach to non-prescribed cannabis use in clinical follow-up of PwP.

Differences in the Presentation and Progression of Parkinson's Disease by Sex.

BACKGROUND: Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. OBJECTIVES: We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data. METHODS: We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. RESULTS: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort. CONCLUSIONS: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management. © 2020 International Parkinson and Movement Disorder Society.

Development of a constitutive and an auto-inducible high-yield expression system for recombinant protein production in the microalga Nannochloropsis oceanica.

Photoautotrophic microalgae offer a great potential as novel hosts for efficient recombinant protein production. Nannochloropsis oceanica produces an extraordinarily high content of polyunsaturated fatty acids, and its robust growth characteristics, published genome sequence and efficient nuclear transformation make N. oceanica a promising candidate for biotechnological applications. To establish a robust and flexible system for recombinant protein production, we cloned six endogenous, potentially constitutive or inducible promoters from N. oceanica strain CCMP1779 and investigated their strength using monomeric Venus as reporter gene. Microscopic pre-screening of individual transformants revealed that the promoters of elongation factor (EF), tubulin (TUB) and nitrate reductase (NR) enabled high reporter gene expression. Comparative quantitative analyses of transformant populations by flow cytometry and qRT-PCR demonstrated the highest Venus expression from the EF promoter and the NR promoter if extended by an N-terminal 14-amino acid leader sequence. The kinetics of reporter gene expression were analysed during photobioreactor cultivation, achieving Venus yields of 0.3% (for EF) and 4.9% (for NR::LS) of total soluble protein. Since inducible expression systems enable the production of toxic proteins, we developed an auto-induction medium for the NR promoter transformants. By switching the N source from ammonium to nitrate in the presence of low ammonium concentrations, the starting point of Venus induction could be fine-tuned and shifted towards exponential growth phase while maintaining high recombinant protein yields. Taken together, we demonstrate that a model recombinant protein can be produced robustly and at very high levels in N. oceanica not only under constitutive but also under auto-inducible cultivation conditions. KEY POINTS: • Nannochloropsis oceanica might serve as host for recombinant protein production. • Comparative promoter strength analyses were conducted for twelve different constructs. • Robust high-yield recombinant protein production was achieved under constitutive conditions. • The nitrate reductase promoter enabled protein production under auto-induction conditions.

DJ-1 is a redox sensitive adapter protein for high molecular weight complexes involved in regulation of catecholamine homeostasis.

DJ-1 is an oxidation sensitive protein encoded by the PARK7 gene. Mutations in PARK7 are a rare cause of familial recessive Parkinson's disease (PD), but growing evidence suggests involvement of DJ-1 in idiopathic PD. The key clinical features of PD, rigidity and bradykinesia, result from neurotransmitter imbalance, particularly the catecholamines dopamine (DA) and noradrenaline. We report in human brain and human SH-SY5Y neuroblastoma cell lines that DJ-1 predominantly forms high molecular weight (HMW) complexes that included RNA metabolism proteins hnRNPA1 and PABP1 and the glycolysis enzyme GAPDH. In cell culture models the oxidation status of DJ-1 determined the specific complex composition. RNA sequencing indicated that oxidative changes to DJ-1 were concomitant with changes in mRNA transcripts mainly involved in catecholamine metabolism. Importantly, loss of DJ-1 function upon knock down (KD) or expression of the PD associated form L166P resulted in the absence of HMW DJ-1 complexes. In the KD model, the absence of DJ-1 complexes was accompanied by impairment in catecholamine homeostasis, with significant increases in intracellular DA and noraderenaline levels. These changes in catecholamines could be rescued by re-expression of DJ-1. This catecholamine imbalance may contribute to the particular vulnerability of dopaminergic and noradrenergic neurons to neurodegeneration in PARK7-related PD. Notably, oxidised DJ-1 was significantly decreased in idiopathic PD brain, suggesting altered complex function may also play a role in the more common sporadic form of the disease.

Genomewide association study of Parkinson's disease clinical biomarkers in 12 longitudinal patients' cohorts.

BACKGROUND: Several reports have identified different patterns of Parkinson's disease progression in individuals carrying missense variants in GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinson's disease, however, has not been well studied. OBJECTIVES: To test the association between genetic variants and the clinical features of Parkinson's disease on a genomewide scale. METHODS: We accumulated individual data from 12 longitudinal cohorts in a total of 4093 patients with 22,307 observations for a median of 3.81 years. Genomewide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently identified disease-risk variants, were also investigated post hoc for candidate associations with these phenotypes. RESULTS: Two variants were genomewide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (hazard ratio 2.04 [1.58-2.62]; P value = 3.46E-8). Rs61863020(G>A), an intergenic variant and expression quantitative trait loci for α-2A adrenergic receptor, was associated with a lower prevalence of insomnia at baseline (odds ratio 0.63 [0.52-0.75]; P value = 4.74E-8). In the targeted analysis, we found 9 associations between known Parkinson's risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K; rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and an APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients. CONCLUSIONS: We identified novel genetic factors associated with heterogeneity of Parkinson's disease. The results can be used for validation or hypothesis tests regarding Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.

Rare genetic variation in mitochondrial pathways influences the risk for Parkinson's disease.

BACKGROUND: Mitochondrial dysfunction plays a key role in PD, but the underlying molecular mechanisms remain unresolved. We hypothesized that the disruption of mitochondrial function in PD is primed by rare, protein-altering variation in nuclear genes controlling mitochondrial structure and function. OBJECTIVE: The objective of this study was to assess whether genetic variation in genes associated with mitochondrial function influences the risk of idiopathic PD. METHODS: We employed whole-exome sequencing data from 2 independent cohorts of clinically validated idiopathic PD and controls, the Norwegian ParkWest cohort (n = 411) and the North American Parkinson's Progression Markers Initiative (n = 640). We applied burden-based and variance-based collapsing methods to assess the enrichment of rare, nonsynonymous, and damaging genetic variants on genes, exome-wide, and on a comprehensive set of mitochondrial pathways, defined as groups of genes controlling specific mitochondrial functions. RESULTS: Using the sequence kernel association test, we detected a significant polygenic enrichment of rare, nonsynonymous variants in the gene-set encoding the pathway of mitochondrial DNA maintenance. Notably, this was the strongest association in both cohorts and survived multiple testing correction (ParkWest P = 6.3 × 10-3 , Parkinson's Progression Markers Initiative P = 6.9 × 10-5 , metaanalysis P = 3.2 × 10-6 ). CONCLUSIONS: Our results show that the enrichment of rare inherited variation in the pathway controlling mitochondrial DNA replication and repair influences the risk of PD. We propose that this polygenic enrichment contributes to the impairment of mitochondrial DNA homeostasis, thought to be a key mechanism in the pathogenesis of PD, and explains part of the disorder's "missing heritability." © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Expression profiling and intracellular localization studies of the novel Proline-, Histidine-, and Glycine-rich protein 1 suggest an essential role in gastro-intestinal epithelium and a potential clinical application in colorectal cancer diagnostics.

BACKGROUND: The primary function of the intestines is the absorption of water and nutrients. Although our knowledge about these processes on the cellular level is extensive, a number of important intracellular elements remain unknown. Here, we characterize the novel proline-, histidine-, glycine-rich 1 (PHGR1) mRNA and protein on the molecular level and propose a functional role of the PHGR1 protein in the intestinal and gastric epithelium. METHODS: PHGR1 mRNA and protein expression in human tissues and cell lines were characterized by quantitative RT-PCR, in situ hybridization, Northern blotting, Western blotting, and immunohistochemistry. Glycosylation was assessed by a chemical deglycosylation assay, whereas intracellular localization was studied by immunofluorescent staining of cell line cells. PHGR1 mRNA levels in HT29 cells was reduced by RNA interference and the resulting global changes in gene expression assessed by microarray hybridization. RESULTS: PHGR1 mRNA and protein were found to be expressed specifically in epithelial cells of intestinal mucosa, with the highest expression in the most mature and differentiated cells. PHGR1 protein was found to be glycosylated and to localize to both the cytoplasm and nucleus. Transcript profiling and gene ontology analysis of HT29 cells subjected to PHGR1 knockdown suggested a functional relationship with transport and metabolic processes. Examination of PHGR1 mRNA and protein levels in lymph nodes with known colorectal cancer metastases indicated that they may serve as biomarkers for detection of such metastases. CONCLUSIONS: Functional analyses of the novel PHGR1 mRNA and protein suggest an essential role in gastrointestinal epithelium and a clinical application in detection of colorectal cancer lymph node metastases.

Association of glucocerebrosidase polymorphisms and mutations with dementia in incident Parkinson's disease.

INTRODUCTION: Both polymorphisms and mutations in glucocerebrosidase (GBA) may influence the development of dementia in patients with Parkinson's disease. METHODS: Four hundred forty-two patients and 419 controls were followed for 7 years. Dementia was diagnosed using established criteria. Participants were analyzed for GBA genetic variants, including E326K, T369M, and L444P. Associations between GBA carrier status and dementia were assessed with Cox survival analysis. RESULTS: A total of 12.0% of patients with Parkinson's disease carried a GBA variant, and nearly half (22/53) of them progressed to dementia during follow-up. Carriers of deleterious GBA mutations (adjusted hazard ratio 3.81, 95% confidence interval 1.35 to 10.72; P = .011) or polymorphisms (adjusted hazard ratio 1.79; 95% confidence interval 1.07 to 3.00; P = .028) progressed to dementia more rapidly than noncarriers. DISCUSSION: GBA variants are of great clinical relevance for the development of dementia in Parkinson's disease, especially due to the relatively higher frequency of these alleles compared with other risk alleles.

Methylation of protein phosphatase 2A-Influence of regulators and environmental stress factors.

Protein phosphatase 2A catalytic subunit (PP2A-C) has a terminal leucine subjected to methylation, a regulatory mechanism conserved from yeast to mammals and plants. Two enzymes, LCMT1 and PME1, methylate and demethylate PP2A-C, respectively. The physiological importance of these posttranslational modifications is still enigmatic. We investigated these processes in Arabidopsis thaliana by mutant phenotyping, by global expression analysis, and by monitoring methylation status of PP2A-C under different environmental conditions. The lcmt1 mutant, possessing essentially only unmethylated PP2A-C, had less dense rosettes, and earlier flowering than wild type (WT). The pme1 mutant, with 30% reduction in unmethylated PP2A-C, was phenotypically comparable with WT. Approximately 200 overlapping genes were twofold upregulated, and 200 overlapping genes were twofold downregulated in both lcmt1 and pme1 relative to WT. Differences between the 2 mutants were also striking; 97 genes were twofold upregulated in pme1 compared with lcmt1, indicating that PME1 acts as a negative regulator for these genes. Analysis of enriched GO terms revealed categories of both abiotic and biotic stress genes. Furthermore, methylation status of PP2A-C was influenced by environmental stress, especially by hypoxia and salt stress, which led to increased levels of unmethylated PP2A-C, and highlights the importance of PP2A-C methylation/demethylation in environmental responses.

Arabidopsis AtPARK13, which confers thermotolerance, targets misfolded proteins.

Mutations in HTRA2/Omi/PARK13 have been implicated in Parkinson disease (PD). PARK13 is a neuroprotective serine protease; however, little is known about how PARK13 confers stress protection and which protein targets are directly affected by PARK13. We have reported that Arabidopsis thaliana represents a complementary PD model, and here we demonstrate that AtPARK13, similar to human PARK13 (hPARK13), is a mitochondrial protease. We show that the expression/accumulation of AtPARK13 transcripts are induced by heat stress but not by other stress conditions, including oxidative stress and metals. Our data show that elevated levels of AtPARK13 confer thermotolerance in A. thaliana. Increased temperatures accelerate protein unfolding, and we demonstrate that although AtPARK13 can act on native protein substrates, unfolded proteins represent better AtPARK13 substrates. The results further show that AtPARK13 and hPARK13 can degrade the PD proteins α-synuclein (SNCA) and DJ-1/PARK7 directly, without autophagy involvement, and that misfolded SNCA and DJ-1 represent better substrates than their native counterparts. Comparative proteomic profiling revealed AtPARK13-mediated proteome changes, and we identified four proteins that show altered abundance in response to AtPARK13 overexpression and elevated temperatures. Our study not only suggests that AtPARK13 confers thermotolerance by degrading misfolded protein targets, but it also provides new insight into possible roles of this protease in neurodegeneration.

Modifying fatty acid profiles through a new cytokinin-based plastid transformation system.

The widespread use of herbicides and antibiotics for selection of transgenic plants has not been very successful with regard to commercialization and public acceptance. Hence, alternative selection systems are required. In this study, we describe the use of ipt, the bacterial gene encoding the enzyme isopentenyl transferase from Agrobacterium tumefaciens, as a positive selectable marker for plastid transformation. A comparison between the traditional spectinomycin-based aadA selection system and the ipt selection system demonstrated that selection of transplastomic plants on medium lacking cytokinin was as effective as selection on medium containing spectinomycin. Proof of principle was demonstrated by transformation of the kasIII gene encoding 3-ketoacyl acyl carrier protein synthase III into tobacco plastids. Transplastomic tobacco plants were readily obtained using the ipt selection system, and were phenotypically normal despite over-expression of isopentenyl transferase. Over-expression of KASIII resulted in a significant increase in 16:0 fatty acid levels, and a significant decrease in the levels of 18:0 and 18:1 fatty acids. Our study demonstrates use of a novel positive plastid transformation system that may be used for selection of transplastomic plants without affecting the expression of transgenes within the integrated vector cassette or the resulting activity of the encoded protein. This system has the potential to be applied to monocots, which are typically not amenable to traditional antibiotic-based selection systems, and may be used in combination with a negative selectable marker as part of a two-step selection system to obtain homoplasmic plant lines.

Parkinson disease protein DJ-1 binds metals and protects against metal-induced cytotoxicity.

The progressive loss of motor control due to reduction of dopamine-producing neurons in the substantia nigra pars compacta and decreased striatal dopamine levels are the classically described features of Parkinson disease (PD). Neuronal damage also progresses to other regions of the brain, and additional non-motor dysfunctions are common. Accumulation of environmental toxins, such as pesticides and metals, are suggested risk factors for the development of typical late onset PD, although genetic factors seem to be substantial in early onset cases. Mutations of DJ-1 are known to cause a form of recessive early onset Parkinson disease, highlighting an important functional role for DJ-1 in early disease prevention. This study identifies human DJ-1 as a metal-binding protein able to evidently bind copper as well as toxic mercury ions in vitro. The study further characterizes the cytoprotective function of DJ-1 and PD-mutated variants of DJ-1 with respect to induced metal cytotoxicity. The results show that expression of DJ-1 enhances the cells' protective mechanisms against induced metal toxicity and that this protection is lost for DJ-1 PD mutations A104T and D149A. The study also shows that oxidation site-mutated DJ-1 C106A retains its ability to protect cells. We also show that concomitant addition of dopamine exposure sensitizes cells to metal-induced cytotoxicity. We also confirm that redox-active dopamine adducts enhance metal-catalyzed oxidation of intracellular proteins in vivo by use of live cell imaging of redox-sensitive S3roGFP. The study indicates that even a small genetic alteration can sensitize cells to metal-induced cell death, a finding that may revive the interest in exogenous factors in the etiology of PD.

Analysis of the chloroplast proteome in arc mutants and identification of novel protein components associated with FtsZ2.

Chloroplasts are descendants of cyanobacteria and divide by binary fission. The number of chloroplasts is regulated in a cell type-specific manner to ensure that specialized cell types can perform their functions optimally. Several protein components of the chloroplast division apparatus have been identified in the past several years, but how this process is regulated in response to developmental status, environmental signals and stress is still unknown. To begin to address this we undertook a proteomic analysis of three accumulation and replication of chloroplasts mutants that show a spectrum of plastid division perturbations. We show that defects in the chloroplast division process results in changes in the abundance of proteins when compared to wild type, but that the profile of the native stromal and membrane complexes remains unchanged. Furthermore, by combining BN-PAGE with protein interaction assays we show that AtFtsZ2-1 and AtFtsZ2-2 assemble together with rpl12A and EF-Tu into a novel chloroplast membrane complex.

Plastid division control: the PDV proteins regulate DRP5B dynamin activity.

Chloroplast division represents a fundamental but complex biological process involving remnants of the ancestral bacterial division machinery and proteins of eukaryotic origin. Moreover, the chloroplast division machinery is divided into stromal and cytosolic sub machineries, which coordinate and control their activities to ensure appropriate division initiation and progression. Dynamin related protein 5B (DRP5B) and plastid division protein 1 and 2 (PDV1 and PDV2) are all plant-derived proteins and represent components of the cytosolic division machinery, where DRP5B is thought to exert constrictional force during division. However, the direct relationship between PDV1, PDV2 and DRP5B, and moreover how DRP5B is regulated during plastid constriction remains unclear. In this study we show that PDV1 and PDV2 can interact with themselves and with each other through their cytosolic domains. We demonstrate that DRP5B interacts with itself and with the cytosolic region of PDV1 and that the two functional isoforms of DRP5B have highly overlapping functions. We further show that DRP5B harbors GTPase activity and moreover that PDV1 and PDV2 inhibits DRP5B-mediated GTP hydrolysis in a ratio dependent manner. Our data suggest that the PDV proteins contribute to the regulation of DRP5B activity thereby enforcing control over the division process during early constriction.

In vivo phosphorylation of FtsZ2 in Arabidopsis thaliana.

The tubulin-like FtsZ protein initiates assembly of the bacterial and plastid division machineries. In bacteria, phosphorylation of FtsZ impairs GTPase activity, polymerization and interactions with other division proteins. Using a proteomics approach, we have shown that AtFtsZ2 is phosphorylated in vivo in Arabidopsis and that PGK1 (phosphoglycerate kinase 1) interacts with AtFtsZ2 in planta, suggesting a possible role in FtsZ phosphorylation.