Biology subjects

Tak, Y.

Publications and source records attributed to Tak, Y..

4 recordsLinked to original sources

bioRxiv2025

Selective Targeting of Pathogenic Tau Seeds via a Novel VHH

In Alzheimers disease (AD) and related tauopathies, progressive pathology has been linked to prion mechanisms, whereby ordered tau assemblies, or "seeds," form in one cell and transit to neighboring or connected cells where they serve as templates for their own replication. Despite intensive efforts to develop early diagnosis and effective treatment, none has emerged. This is due partly to the structural heterogeneity of tau seeds and limitations in selectively targeting their pathogenic conformations. Here we report the discovery of a camelid variable heavy domain of heavy chain (VHH) that preferentially binds tau seeds of AD, corticobasal degeneration (CBD), and PS19 tauopathy mouse brains. From a published synthetic VHH yeast display library, we identified VHH clones that bound 2N4R tau monomer. After counter-screening for immunoprecipitation of seeding from human brain, we identified two seed-selective anti-tau VHH--VHH(510) and VHH(50)--that preferentially bound pathological tau. We enhanced the stability of these VHHs through framework mutations without affecting their seed-binding characteristics. We characterized VHH(510) in detail, determining that it binds the carboxy terminus of tau, maintains robust seed avidity even in the presence of competing monomer, and stains pathological tau inclusions in mouse and human AD tissues. These results highlight the power of seed-selective VHH to bind pathogenic tau, paving the way for future therapeutic and diagnostic applications across a wide range of neurodegenerative disorders.

neuroscience↗

bioRxiv2024

Essential tremor with tau pathology features seeds indistinguishable in conformation from Alzheimer's disease and primary age-related tauopathy

Neurodegenerative tauopathies are characterized by the deposition of distinct fibrillar tau assemblies whose rigid core structures correlate with defined neuropathological phenotypes. Essential tremor (ET) is a progressive neurological disease disease that, in some cases, is associated with cognitive impairment and tau accumulation.. Consequently, we explored the tau assembly conformation in ET patients with tau pathology using cytometry-based tau biosensor assays. These assays quantify tau prion seeding activity present in brain homogenates based on conversion of intracellular tau-fluorescent protein fusions from a soluble to an aggregated state. Prions exhibit seeding barriers, whereby a specific assembly structure cannot serve as a template for a native monomer if the amino acids are not compatible. We recently exploited the tau prion species barrier to define tauopathies by systematically substituting alanine (Ala) in the tau monomer and measuring its incorporation into seeded aggregates within biosensor cells. The Ala scan precisely classified the conformation of tau seeds from diverse tauopathies. We next studied 18 ET patient brains with tau pathology. Only one case had concurrent high amyloid-{beta} plaque pathology consistent with Alzheimers disease (AD). We detected robust tau seeding activity in 9 (50%) of the patients. This predominantly localized to the temporal pole and temporal cortex. We examined 8 ET cases with the Ala scan and determined that the amino acid requirements for tau monomer incorporation into aggregates seeded from these ET brain homogenates were identical to those of AD and primary age-related tauopathy (PART), and completely distinct from other tauopathies such as corticobasal degeneration, chronic traumatic encephalopathy, and progressive supranuclear palsy. Based on these studies, tau assembly cores in a pathologically confined subset of ET cases with high tau pathology are identical to AD and PART. This could facilitate more precise diagnosis and therapy for ET patients with cognitive impairment.

pathology↗

bioRxiv2020

Identification of subfunctionalized aggregate-remodeling J-domain proteins in plants

Hsp70s and J-domain proteins (JDPs) are among the most critical components of the cellular protein quality control machinery, playing crucial roles in preventing and solubilizing cytotoxic protein aggregates. Bacteria, yeast and plants additionally have large, multimeric Hsp100-class disaggregases which, allow the resolubilization of otherwise "dead-end" aggregates, including amyloids. JDPs interact with aggregated proteins and specify the aggregate remodeling activities of Hsp70s and Hsp100s. Plants have a complex network of cytosolic Hsp70s and JDPs, however the aggregate remodeling properties of plant JDPs are not well understood. Here we identify evolutionary-conserved Class II JDPs in the model plant Arabidopsis thaliana with distinct aggregate remodeling functionalities. We identify eight plant orthologs of the yeast protein, Sis1, the principal JDP responsible for directing the yeast chaperone machinery for remodeling protein aggregates. Expression patterns vary dramatically among the eight paralogous proteins under a variety of stress conditions, indicating their subfunctionalization to address distinct stressors. Consistent with a role in solubilizing cytotoxic protein aggregates, six of these plant JDPs associate with heat-induced protein aggregates in vivo as well as colocalize with plant Hsp101 to distinct heat-induced protein aggregate centers. Finally, we show that these six JDPs can differentially remodel multiple model protein aggregates in yeast confirming their involvement in aggregate resolubilization. These results demonstrate that compared to complex metazoans, plants have a robust network of JDPs involved in aggregate remodeling activities with the capacity to process a variety of protein aggregate conformers.

molecular biology↗

bioRxiv2020

Striatal cholinergic interneuron numbers are increased in a rodent model of dystonic cerebral palsy

Neonatal brain injury leading to cerebral palsy (CP) is the most common cause of childhood dystonia, a painful and functionally debilitating movement disorder. Rare monogenic etiologies of dystonia have been associated with striatal cholinergic interneuron (ChI) pathology. However it is unclear whether striatal ChI pathology is also associated with dystonia following neonatal brain injury. We used unbiased stereology to estimate striatal ChI and parvalbumin-positive GABAergic interneuron (PVI) numbers in a rodent model of neonatal brain injury that demonstrates electrophysiological markers of dystonia and spasticity. Striatal ChI numbers are increased following neonatal brain injury while PVI numbers are unchanged. These numbers do not correlate with electrophysiologic measures of dystonia severity. This suggests that striatal ChI pathology, though present, may not be the primary pathophysiologic contributor to dystonia following neonatal brain injury. Increased striatal ChI numbers could instead represent a passenger or protective phenomenon in the setting of dystonic CP.

neuroscience↗