Description

The Grinberg lab serves as the human biology validation core for the NIH-funded https://cwow.ucsf.edu/. As the human biology validation core, the Grinberg lab directly supports all projects in the study by validating results in human specimens, relying on well-characterized and carefully preserved tissue, bio-fluids, and cells from tauopathy patients and controls. Additionally, the Grinberg lab develops enhanced tools for conducting state-of-the-art multiplex assays in human specimens, thus allowing the scaling of the in vitro assays.

Tauopathy is a prevalent and devastating neurodegenerative condition in the elderly. Tauopathies include Alzheimer’s disease (AD) and frontotemporal lobar degeneration with tau inclusions (FTLD-tau), a major subtype of FTLD characterized by changes in behavior, difficulty with language, and problems with body movement. Tauopathies are untreatable. A better understanding of their pathogenesis is urgently needed to develop novel treatments.

Tauopathy is characterized by the accumulation and spread of pathogenic forms, key features of imbalances in tau levels. Thus, how tau becomes imbalanced and the functional outcome of such an imbalance are at the core of tau pathogenesis. West cWOW scientists hypothesize that there is a connection between tau imbalance and neuronal dysfunction. Understanding this connection would shed new insights into mechanisms underlying tau pathogenesis.

The center’s researchers aim to address three fundamental questions:

1. What causes tau to accumulate and spread in FTD?
   Accumulation of tau inside cells, as well as spreading between cells, are two interconnected key features of tau imbalance. For tau accumulation, the scientists will address the role of tau mutations and tau fibrils using a combination of proteomic, transcriptomic, and hypothesis-driven approaches. For tau spread, they will systematically analyze the mechanisms underlying the following processes: release, uptake, and seeding (uptake that alters endogenous tau).

2. How does imbalanced tau levels induce neuronal dysfunction in FTD?
   Although insoluble tau is often the hallmark of tauopathy, soluble tau (e.g. those that are improperly modified) could also be important in inducing neuronal dysfunction. The center will address the functional toxicity of both soluble tau and insoluble tau fibrils using a combination of traditional electrophysiology recordings and multi-electrode array for network activities.

3. How does neuronal activity modulate tau imbalance in FTD?
   Both in vitro and in vivo studies showed that the release of tau is activity-dependent. The aberrant neuronal activity could serve as a feedback loop, further amplifying the tau imbalances in FTD. The scientists will test this hypothesis using innovative approaches that combine proteomic/transcriptome analyses with neuronal activity modulation.

Funding source(s)

“This research was supported by the National Institute on Aging and the National Institute of Neurological Disorders and Stroke, National Institutes of Health, grant U54NS123746.”

Related publications

Acetylated tau destabilizes the cytoskeleton in the axon initial segment and is mislocalized to the somatodendritic compartment.

Molecular neurodegeneration
2016
Sohn PD, Tracy TE, Son HI, Zhou Y, Leite RE, Miller BL, Seeley WW, Grinberg LT, Gan L