Are ATXN2 variants modifying our understanding about neural pathogenesis,phenotypes,and diagnostic?

ATXN2 one gene with multiple phenotype effects:ATXN2 gene encodes a cytosolic protein(ataxin-2)with pleiotropic functions(see below).This gene contains a number of exonic Cytosine-Adenine-Guanine(CAG)-repeats which encodes a polyglutamine tract(polyQ)in the N-terminal intrinsically disordered region(IDR)of the protein.ATXN2CAG repeats are interrupted by CAA codons which is relevant only for DNA and RNA but not for protein since CAA also encodes glutamine(Q).

Large-scale proximity extension assay reveals CSF midkine and DOPA decarboxylase as supportive diagnostic biomarkers for Parkinson’s disease

Background There is a need for biomarkers to support an accurate diagnosis of Parkinson’s disease(PD).Cerebrospinal fluid(CSF)has been a successful biofluid for finding neurodegenerative biomarkers,and modern highly sensitive multiplexing methods offer the possibility to perform discovery studies.Using a large-scale multiplex proximity extension assay(PEA)approach,we aimed to discover novel diagnostic protein biomarkers allowing accurate discrimination of PD from both controls and atypical Parkinsonian disorders(APD).Methods CSF from patients with PD,corticobasal syndrome(CBS),progressive supranuclear palsy(PSP),multiple system atrophy and controls,were analysed with Olink PEA panels.Three cohorts were used in this study,comprising 192,88 and 36 cases,respectively.All samples were run on the Cardiovascular II,Oncology II and Metabolism PEA panels.Results Our analysis revealed that 26 and 39 proteins were differentially expressed in the CSF of test and validation PD cohorts,respectively,compared to controls.Among them,6 proteins were changed in both cohorts.Midkine(MK)was increased in PD with the strongest effect size and results were validated with ELISA.Another most increased protein in PD,DOPA decarboxylase(DDC),which catalyses the decarboxylation of DOPA(L-3,4-dihydroxyphenylalanine)to dopamine,was strongly correlated with dopaminergic treatment.Moreover,Kallikrein 10 was specifically changed in APD compared with both PD and controls,but unchanged between PD and controls.Wnt inhibitory factor 1 was consistently downregulated in CBS and PSP patients in two independent cohorts.Conclusions Using the large-scale PEA approach,we have identified potential novel PD diagnostic biomarkers,most notably MK and DDC,in the CSF of PD patients.

Ecto-GPR37:a potential biomarker for Parkinson’s disease

Objective:a-Synuclein has been studied as a potential biomarker for Parkinson's disease(PD)with no concluding results.Accordingly,there is an urgent need to find out reliable specific biomarkers for PD.GPR37 is an orphan G protein-coupled receptor that toxically accumulates in autosomal recessive juvenile parkinsonism.Here,we investigated whether GPR37 is upregulated in sporadic PD,and thus a suitable potential biomarker for PD.Methods:GPR37 protein density and mRNA expression in postmortem substantia nigra(SN)from PD patients were analysed by immunoblot and RT-qPCR,respectively.The presence of peptides from the N-terminus-cleaved domain of GPR37(i.e.ecto-GPR37)in human cerebrospinal fluid(CSF)was determined by liquid chromatography-mass spectrometric analysis.An engineered in-house nanoluciferase-based immunoassay was used to quantify ecto-GPR37 in CSF samples from neurological control(NC)subjects,PD patients and Alzheimer's disease(AD)patients.Results:GPR37 protein density and mRNA expression were significantly augmented in sporadic PD.Increased amounts of ecto-GPR37 peptides in the CSF samples from PD patients were identified by mass spectrometry and quantified by the in-house ELISA method.However,the CSF total a-synuclein level in PD patients did not differ from that in NC subjects.Similarly,the cortical GPR37 mRNA expression and CSF ecto-GPR37 levels in AD patients were also unaltered.Conclusion:GPR37 expression is increased in SN of sporadic PD patients.The ecto-GPR37 peptides are significantly increased in the CSF of PD patients,but not in AD patients.These results open perspectives and encourage further clinical studies to confirm the validity and utility of ecto-GPR37 as a potential PD biomarker.