The pathogenesis of Amyotrophic Lateral Sclerosis.
Frontotemporal Dementia and similar age-dependent neurodegenerative diseases.
The Donnelly Lab is in the Department of Neurobiology at the University of Pittsburgh School of Medicine and the LiveLikeLou Center for ALS Research in the Universtiy of Pittsburgh Brain Institute.
We seek to understand the pathobiology underlying neurodegenerative diseases with a particular interest in the progressive and fatal motor neuron disease, Amyotrophic Lateral Sclerosis (ALS). Our lab employs a molecular and cellular approach that includes the use of induced pluripotent stem cell cultures (iPSCs) from patients, gene editing, optogenetics, longitudinal and confocal microscopy, RNA imaging, and protein biochemistry. We use these tools to investigate genetic and molecular perturbations in these cellular processes that contribute to age-dependent neurodegeneration observed in ALS, FTD, and Alzheimer’s Disease.
We are interested in how perturbations in cellular processes drive neurodegeneration including, RNA metabolism, subcellular RNA and protein trafficking in neurons, and intracellular liquid-liquid phase separation of membraneless organelles. A common neuropathological feature of neurodegenerative diseases is the presence of intracellular protein aggregates, such as the TDP-43 protein. Therefore, we are particularly interested in understanding how dysfunction in RNA processing, subcellular trafficking, and aberrant liquid-liquid phase separation drive neurotoxic protein misfolding and to develop strategies to intervene in this neurotoxic process.
Representative Publications
Muscleblind acts as a modifier of FUS toxicity by modulating stress granule dynamics and SMN localization. .
Casci l, Krishnamurthy K, Kour S, Tripathy V, Ramesh N, Anderson EN, Marrone L, Grant RA, Oliver S, Gochenaur L, Patel K, Sterneckert J, Glexiner AM, Donnelly CJ, Ruepp MD, Sini AM, Zuccaro E, Pennuto M, Pasinelli P, Pandey UB,
Nature Communications (2019)
RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43.
Mann JR, Gleixner AM, Mauna JC, Gomes E, DeChellis-Marks MR, Needham PG, Copley KE, Hurtle B, Portz B, Pyles NJ, Guo L, Calder CB, Wills ZP, Pandey UB, Kofler JK, Brodsky JL, Thathiah A, Shorter J, Donnelly CJ
Neuron (2019)
The C9orf72 repeat expansion disrupts nucleocytoplasmic transport.
Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD
Nature (2015)
C9orf72 nucleotide repeat structures initiate molecular cascades of disease.
Haeusler AR, Donnelly CJ, Periz G, Simko EA, Shaw PG, Kim MS, Maragakis NJ, Troncoso JC, Pandey A, Sattler R, Rothstein JD, Wang J
Nature (2014)
RNA toxicity from the ALS/FTD C9orf72 expansion is mitigated by antisense intervention.
Donnelly CJ, Zhang PW, Pham JT, Haeusler AR, Mistry NA, Vidensky S, Daley EL, Poth EM, Hoover B, Fines DM, Maragakis NJ, Tienari PJ, Petrucelli L, Traynor BJ, Wang J, Rigo F, Bennett CF, Blackshaw S, Sattler R, Rothstein JD
Neuron (2013)
Axonally synthesized b-actin and GAP-43 proteins support distinct modes of axonal growth.
Donnelly CJ, Park M, Spillane M, Yoo S, Pacheco A, Gomes C, Vuppalanchi D, McDonald M, Kim HH, Merianda TT, Gallo G, Twiss JL
Journal of Neuroscience (2013)
Limited availability of ZBP1 restricts axonal mRNA localization and nerve regeneration capacity.
Donnelly CJ, Willis DE, Xu M, Tep C, Jiang C, Yoo S, Schanen NC, Kirn-Safran CB, van Minnen J, English A, Yoon SO, Bassell GJ, Twiss JL
EMBO Journal (2011)