Highlights d Autoinhibited (3.3 Å ) and active (6.8 Å ) structures of prodegenerative NADase SARM1 solved d Identification of a critical autoinhibitory lock d Lock mutations convert inactive SARM1 to an active, neurotoxic state d Enzymatic studies explain SARM1's functional dependence on local metabolic environment

Tau aggregates are present in multiple neurodegenerative diseases known as “tauopathies,” including Alzheimer’s disease, Pick’s disease, progressive supranuclear palsy, and corticobasal degeneration. Such misfolded tau aggregates are therefore potential sources for selective detection and biomarker discovery. Six human tau isoforms present in brain tissues and both 3R and 4R isoforms have been observed in the neuronal inclusions. To develop selective markers for AD and related rare tauopathies, we first used an engineered tau protein fragment 4RCF as the substrate for ultrasensitive real-time quaking-induced conversion analyses (RT-QuIC). We showed that misfolded tau from diseased AD and other tauopathy brains were able to seed recombinant 4RCF substrate. We further expanded to use six individual recombinant tau isoforms as substrates to amplify misfolded tau seeds from AD brains. We demonstrated, for the first time to our knowledge, that misfolded tau from the postmortem AD brain tissues was able to specifically seed all six full-length human tau isoforms. Our results demonstrated that RT-QuIC analysis can discriminate AD and other tauopathies from non-AD normal controls. We further uncovered that 3R-tau isoforms displayed significantly faster aggregation kinetics than their 4R-tau counterparts under conditions of both no seeding and seeding with AD brain homogenates. In summary, our work offers potential new avenues of misfolded tau detection as potential biomarkers for diagnosis of AD and related tauopathies and provides new insights into isoform-specific human tau aggregation.

Tau aggregates are present in a large number of neurodegenerative diseases known as "tauopathies", including Alzheimer's disease (AD). As there are six human tau isoforms in brain tissues and both 3R and 4R isoforms have been observed in the neuronal inclusions, we tested whether tau isoforms behave differently in aggregation. We discovered that all six tau isoforms are capable of forming PHF-tau like filaments and the 3R tau isoforms aggregate significantly faster than their 4R counterparts. We further mapped key segments of tau isoforms that contribute to their aggregation kinetics, where it was determined that microtubule binding domains R2 and R3 were the major contributors to tau aggregation. To evaluate the feasibility of using the six recombinant tau isoforms as substrates to amplify misfolded tau, we demonstrated that full-length human tau isoforms can seed and detect misfolded tau from the post-mortem AD brain tissues with high specificity by an ultrasensitive technology termed real-time quaking-induced conversion (RT-QuIC). Mass spectrometric analysis of PHF-tau samples extracted from AD brains identified peptides corresponding to all major forms of human brain tau isoforms along with a consensus hyperphosphorylated peptide near the C-terminus.Together, our findings not only reveal new aggregation kinetic properties of human tau isoforms, support the development of methods to quantitatively measure misfolded human tau isoforms in AD brains, but also uncover the capability of full-length human tau isoforms as substrates for "prion-like" tau seeding by RT-QuIC assays that may be used for new biomarker development for AD and other tauopathy diagnosis.

INTRODUCTION: Early detection of leptomeningeal metastases (LM) with paediatric brain tumors cases can change the prognosis as well as course of treatment. Conventional MR imaging and CSF (cerebrospinal fluid) analysis plays a vital role in detection of metastases, however, due to certain limitations these can be missed. In our study, diffusion weighed imaging (DWI) of spine was able to bridge this gap and increased the detection rate in MRI equivocal cases in which CSF study was negative. AIMS: To evaluate the incremental value of DWI over the conventional sequences in detection of LM. MATERIALS & METHODS: Paediatric patients with primary brain tumors known to show restriction and propensity for CSF metastasis underwent MRI on 1.5T Philip’s machine. CSF analysis and radiological follow up were used to confirm the diagnosis. RESULTS: Of the 26 patients proven to have LM, linear leptomeningeal metastases (LLP) were seen in 7 patients and nodular leptomeningeal metastases (NLM) were seen in 6 patients and both were seen in 13 patients. Of the 20 patients with LLM, 18 were detected on contrast; however, these were not detected on T2W and DWI except one patient with thick LLP. In 19 patients with NLM, a total of 84 lesions were detected. All were appreciated on contrast with additional 6 lesions which were false positive (FP). Total 96 lesions were detected on T2W, of which 80 were true positive and 16 were FP. About 80 lesions were detected on DWI. Thus, on contrast sequence FP were 6 while on T2W 16 were FP. DISCUSSION: DWI showed a lower FP rate than conventional sequences. CONCLUSION: Contrast sequence remains most reliable sequence for the detection of LM. However, DWI is useful in equivocal cases. The role of DWI in Group 3 and 4 Medulloblastoma with non-enhancing metastases needs to be further explored.