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Background Autosomal dominant mutations in α-synuclein, TDP-43 and tau are thought to predispose to neurodegeneration by enhancing protein aggregation. While a subset of α-synuclein, TDP-43 and tau mutations has been shown to increase the structural propensity of these proteins toward self-association, rates of aggregation are also highly dependent on protein steady state concentrations, which are in large part regulated by their rates of lysosomal degradation. Previous studies have shown that lysosomal proteases operate precisely and not indiscriminately, cleaving their substrates at very specific linear amino acid sequences. With this knowledge, we hypothesized that certain coding mutations in α-synuclein, TDP-43 and tau may lead to increased protein steady state concentrations and eventual aggregation by an alternative mechanism, that is, through disrupting lysosomal protease cleavage recognition motifs and subsequently conferring protease resistance to these proteins. Results To test this possibility, we first generated comprehensive proteolysis maps containing all of the potential lysosomal protease cleavage sites for α-synuclein, TDP-43 and tau. In silico analyses of these maps indicated that certain mutations would diminish cathepsin cleavage, a prediction we confirmed utilizing in vitro protease assays. We then validated these findings in cell models and induced neurons, demonstrating that mutant forms of α-synuclein, TDP-43 and tau are degraded less efficiently than wild type despite being imported into lysosomes at similar rates. Conclusions Together, this study provides evidence that pathogenic mutations in the N-terminal domain of α-synuclein (G51D, A53T), low complexity domain of TDP-43 (A315T, Q331K, M337V) and R1 and R2 domains of tau (K257T, N279K, S305N) directly impair their own lysosomal degradation, altering protein homeostasis and increasing cellular protein concentrations by extending the degradation half-lives of these proteins. These results also point to novel, shared, alternative mechanism by which different forms of neurodegeneration, including synucleinopathies, TDP-43 proteinopathies and tauopathies, may arise. Importantly, they also provide a roadmap for how the upregulation of particular lysosomal proteases could be targeted as potential therapeutics for human neurodegenerative disease.

Lake Fryxell, McMurdo Dry Valleys, Antarctica contains a constantly cold water column and perennial ice-cover. Although carbon and sulfur cycling in this amictic lake have been studied previously, a paired investigation of 16S rRNA gene based microbial diversity and geochemistry of Lake Fryxell is lacking. Here, we used a combination of radiotracer-based rate measurements, geochemical measurements, and molecular microbial community analysis to investigate the anaerobic oxidation of methane (AOM) and associated processes in Lake Fryxell. The results show that while AOM and sulfate reduction appear coupled in the upper regions of the anoxic water column, in deep anoxic waters, where AOM rates are highest, sulfate is unlikely to be the electron acceptor for AOM. Despite significant rates of AOM in these waters, no putative AOM-associated Archaea or Bacteria were observed. Due to a lack of documented AOM electron acceptors and putative ANMEs, we suggest novel modes of AOM dominate in this extreme environment. First, the notable abundance of the bacterial genus Dehalococcoides suggests that reductive dehalogenation could fuel AOM. Further, taxa of the candidate phylum OP9, the Atribacteria, and the Bathyarchaeota (formerly known as the Miscellaneous Crenarchaeotal Group) both commonly observed at cold methane-seeps globally, may mediate AOM, possibly using humic acids as electron shuttles, in Lake Fryxell.

Documenting anaerobic microbial metabolisms in hypersaline perennially ice-covered lakes in Antarctica further refines the environmental limits to life and may reveal rare biogeochemical mechanisms and/or novel microbial catalysts of elemental cycling. We assessed rates of sulfate reduction, methanogenesis, and anaerobic oxidation of methane using radiotracers and generated 16S rRNA gene libraries from the microbial communities inhabiting the deep calcium-chloride-rich brine and sediments of Lake Vanda, McMurdo Dry Valleys, Antarctica. Sulfate reduction rates were observed in surface sediments but not in the brine overlying the sediments. Methane formation through the methylotrophic, acetoclastic, and hydrogenotrophic pathways was quantified using 14C-labeled methylamine, acetate, and CO₂, respectively, and methanogenesis was detected in both the brine and the sediments. Hydrogenotrophic methanogenesis rates were the highest of all substrates tested in the sediments, while methylotrophic methanogenesis was highest in the brines. Anaerobic oxidation of methane was below the limit of detection in both the brines and sediments. The major taxa of Bacteria and Archaea detected were most similar to organisms previously observed in hypersaline environments and included examples related to known sulfate-reducing bacteria other than Deltaproteobacteria (surprisingly, sulfate-reducing Deltaproteobacteria were not observed in this study), and both methanogenic and methanotrophic Archaea. These data indicate an active microbial community in the anoxic brine of Lake Vanda that while similar in terms of community structure and metabolism to other brine habitats, is uniquely evolved to survive in this extreme environment.

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.