Michael Metrick

• MD PhD
• Resident at University of California, San Francisco

Background The microtubule‐associated protein tau is implicated in the development of a class of diverse neurodegenerative disorders, referred to as tauopathies, with symptoms of dementia and parkinsonism. Tauopathies comprise more than 20 clinicopathological entities, including Alzheimer’s disease, which accounts for 70% of dementia cases worldwid...

Background Emerging evidence indicates leucine‐rich repeat kinase 2 (LRRK2) may be involved in tau uptake and spread throughout the brain. Microglia, the brain‐resident phagocytes, become one of the highest LRRK2 expressing cells under inflammatory conditions. Rodent microglia were also shown capable of secreting seeding‐competent tau into the extr...

The accurate recapitulation in an in vitro assay of the aggregation process of α-synuclein in Parkinson's disease has been a significant challenge. As α-synuclein does not aggregate spontaneously in most currently used in vitro assays, primary nucleation is triggered by the presence of surfaces such as lipid membranes or interfaces created by shaki...

The aggregation of the protein tau into amyloid fibrils is associated with Alzheimer’s disease and related tauopathies. Since different tauopathies are characterised by the formation of distinct tau fibril polymorphs, it is important to develop in vitro tau aggregation assays that recapitulate the mechanism of tau aggregation in the brain, resultin...

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are distinct clinicopathological subtypes of frontotemporal lobar degeneration. They both have atypical parkinsonism, and they usually have distinct clinical features. The most common clinical presentation of PSP is Richardson syndrome, and the most common presentation of CBD...

The microtubule-stabilising protein tau misfolds and accumulates into amyloid inclusions in a diverse class of diseases called tauopathies. A growing body of biochemical and structural literature has now confirmed that tau takes different disease-specific aggregate conformations, which then propagate throughout the brains of afflicted patients. The...

The expansion of structural databases and the increase in computing power are enabling approaches for antibody discovery based on computational design. It has already been shown that it is possible to use this approach to generate antibodies for specific epitopes on challenging targets. Here we describe an application of this procedure for antibody...

Efforts to contain the spread of chronic wasting disease (CWD), a fatal, contagious prion disease of cervids, would be aided by the availability of additional diagnostic tools. RT-QuIC assays allow ultrasensitive detection of prion seeds in a wide variety of cervid tissues, fluids and excreta. The best documented antemortem diagnostic test involvin...

Supplementary materials from the manuscript: A single ultrasensitive assay for detection and discrimination of tau aggregates of Alzheimer and Pick diseases

Multiple neurodegenerative diseases are characterized by aggregation of tau molecules. Adult humans express six isoforms of tau that contain either 3 or 4 microtubule binding repeats (3R or 4R tau). Different diseases involve preferential aggregation of 3R (e.g Pick disease), 4R (e.g. progressive supranuclear palsy), or both 3R and 4R tau molecules...

To address the need for more meaningful biomarkers of tauopathies, we have developed an ultrasensitive tau seed amplification assay (4R RT-QuIC) for the 4-repeat (4R) tau aggregates of progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and other diseases with 4R tauopathy. The assay detected seeds in 106–109-fold dilutions of 4R...

The original version of this article unfortunately contained a mistake. The Panel A in the published figure 5 is incorrect. The corrected Figure 5 is placed in the following page.

Supplementary material for: Million-fold sensitivity enhancement in proteopathic seed amplification assays for biospecimens by Hofmeister ion comparisons

Significance Detection of aggregated proteins in human tissues represents a challenging, yet proven, avenue for diagnosing neurodegenerative diseases. For therapeutic advances to occur, an accurate and early diagnosis must be made, which would ideally rely on a biomarker that can track the progression of the disease. One challenging aspect to this...

Chronic wasting disease (CWD) is a fatal prion disease which affects cervids. This disease has an asymptomatic incubation time of 2-4 years, and during this period cervids can shed prions through saliva, feces, urine and placental tissue, contaminating the environment. Indeed, CWD is highly contagious between cervids and shedding from live, infecte...

Alzheimer disease (AD) and chronic traumatic encephalopathy (CTE) involve the abnormal accumulation in the brain of filaments composed of both three-repeat (3R) and four-repeat (4R) (3R/4R) tau isoforms. To probe the molecular basis for AD’s tau filament propagation and to improve detection of tau aggregates as potential biomarkers, we have exploit...

The abnormal assembly of tau, α-synuclein (αSyn), or prion protein into oligomers and multimers underpins the molecular pathogenesis of multiple neurodegenerative diseases. Such pathological aggregates can often grow by seeded polymerization mechanisms. We and others have taken advantage of these mechanisms to amplify seeding activities in vitro an...

Sedimentation equilibrium (SE) analytical ultracentrifugation (AUC) is a gold standard for the rigorous determination of macromolecular buoyant molar masses and the thermodynamic study of reversible interactions in solution. A significant experimental drawback is the long time required to attain SE, which is usually on the order of days. We have de...

Circular dichroism (CD) and attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopies were used to study how sucrose and salts, NaCl, NaClO4, Na2SO4, CaCl2, MgCl2, MgSO4, and NH4Cl alter lysozyme and myoglobin solvation and thermal stability. Both proteins follow the anionic Hofmeister series in which chaotropes (Cl−, ClO4−)...

Sedimentation equilibrium (SE) analytical ultracentrifugation is a gold standard for the rigorous thermodynamic study of buoyant molecular weight and reversible interactions of macromolecules in solution. A significant drawback is the long experiment time, as it takes days to attain SE with standard solution columns. We have developed a new method...

RecA is an Escherichia coli protein that catalyzes the strand exchange reaction utilized in DNA repair. Previous studies have shown that the presence of salts influence RecA activity, aggregation, and stability. Here we utilized attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy and circular dichroism (CD) to further in...

RecA is a DNA repair protein found in Escherichia coli, with homologues found in mammalian species. RecA is a DNA dependent ATPase that hydrolyzes ATP in the presence of single or double-stranded DNA. RecA has pH dependent affinities for ssDNA and dsDNA binding and ATP hydrolysis. Previous studies in our laboratory have shown that a variety of salt...