Bess Frost, Ph.D.Assistant Professor
University of California San Francisco, 2009
A major focus of the laboratory is on tauopathy. Tauopathies, including Alzheimer's disease, are characterized by the deposition of tau protein aggregates in the brains of affected individuals. Motivated by our previous identification of relaxation of heterochromatic DNA as a novel disease mechanism in tauopathies, we are currently pursuing the following areas of study:
1. Laminopathies are disorders caused by mutations in genes encoding lamins. Phenotypically, laminopathies include accelerated aging or "progeroid" syndromes alongside cellular abnormalities such as misshapen nuclei and loss of heterochromatin organization. Our current studies suggest that lamin misregulation though aberrant cytoskeletal-nucleoskeletal coupling drives heterochromatin relaxation in tauopathies (Figure 1). Our work identifies the lamin nucleoskeleton as a molecular link between aging, neurodegeneration, and basic mechanisms of cellular senescence.
2. Chromosomal regions in close proximity to telomeres and centromeres are packaged into tightly wound DNA termed "constitutive heterochromatin," which is rich in transposable element sequences. PIWI-interacting RNAs (piRNAs) are an abundant class of small noncoding RNAs that silence transposable element expression. While piRNAs have been implicated in establishing long-term memory, the role of piRNAs in the brain remains largely unexplored. We are currently interested in piRNA and transposable element misregulation as a consequence of heterochromatin relaxation in tauopathies.
Frost B, Bardai FH, Feany, MB (2016) Lamin Dysfunction Mediates Neurodegeneration in Tauopathies. Curr Biol. Jan 11;26(1):129-36.
Frost B, Hemberg M, Lewis J, Feany MB. (2014) Tau promotes neurodegeneration through global chromatin relaxation. Nat Neurosci. Mar;17(3):357-66.
Merlo P, Frost B, Peng S, Yang YJ, Park PJ, Feany M. (2014) p53 prevents neurodegeneration by regulating synaptic genes. Proc Natl Acad Sci U S A. Dec 16;111(50):18055-60.
Frost B, Diamond MI. (2010) Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci. Mar;11(3):155-9.
Frost B, Jacks RL, Diamond MI. (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem. May 8;284(19):12845-52.
Frost B, Ollesch J, Wille H, Diamond MI. (2009) Conformational diversity of wild-type Tau fibrils specified by templated conformation change. J Biol Chem. Feb 6;284(6):3546-51.