The molecular pathogenesis of Amyotrophic Lateral Sclerosis, Frontotemporal Dementia and similar age-dependent neurodegenerative diseases.
Our laboratory employs induced pluripotent stem cell (iPSC) neurons and glia derived from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients to study the molecular pathogenesis of neurodegeneration and aging. Specifically, we study the mechanisms that underlie nuclear pore biology and nucleocytoplasmic trafficking dysfunction in ALS/FTD and other TDP-43 proteinopathies. The goals of this work is to to uncover novel mechanisms that lead to selective neurodegeneration and to develop methods of intervention to prevent trafficking-related neural injury. Our current studies include: 1) to identify intrinsic differences in the nuclear pore composition in neural subtypes; 2) develop models to link neural subtype specific nuclear pores and trafficking deficits to selective neurodegeneration; 3) to therapeutically rescue trafficking defects in vivo using novel and existing models of neurodegeneration; and 4) to assess retrograde axon survival signaling and length sensing in the context of ALS/FTD-induced nucleocytoplasmic trafficking defects. Long-term studies include understanding the pathobiology of nuclear pore dysfunction in age-dependent and acute TDP-43 proteinopathies including subsets of Alzheimer’s disease and chronic traumatic encephalopathy patients (CTE).
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. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):56-61. PubMed PMID: 26308891 *Authors share equal contribution
Haeusler AR, Donnelly CJ, Periz G, Simko EA, Shaw PG, Kim MS, Maragakis NJ, Troncoso JC, Pandey A, Sattler R, Rothstein JD, Wang J. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature. 2014 Mar 13;507(7491):195-200. PubMed PMID: 24598541; PubMed Central PMCID: PMC4046618
Donnelly CJ, Zhang PW, Pham JT, Haeusler AR, Mistry NA, Vidensky S, Daley EL, Poth EM, Hoover B, Fines DM, Maragakis N, Tienari PJ, Petrucelli L, Traynor BJ, Wang J, Rigo F, Bennett CF, Blackshaw S, Sattler R, Rothstein JD. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron. 2013 Oct 16;80(2):415-28. PubMed PMID: 2413902; PubMed Central PMCID: PMC4098943.
Donnelly CJ, Park M, Spillane M, Yoo S, Pacheco A, Gomes C, Vuppalanchi D, McDonald M, Kim HH, Merianda TT, Gallo G, Twiss JL. Axonally synthesized ß-actin and GAP-43 proteins support distinct modes of axonal growth. J Neurosci. 2013 Feb 20;33(8):3311-22. PubMed PMID: 23426659; PubMed Central PMCID: PMC3711152.
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. Limited availability of ZBP1 restricts axonal mRNA localization and nerve regeneration capacity. EMBO J. 2011 Sep 30;30(22):4665-77. PubMed PMID: 21964071; PubMed Central PMCID: PMC3243598. *Authors share equal contribution