PostDoc in Nuclear biology of Neurodegeneration

We are looking for highly motivated postdoctoral candidates to participate in studies of the pathophysiology of nuclear transport and the nuclear pore complex in neurodegenerative disorders including in ALS and dementias in the laboratory of Jeffrey Rothstein MD, PhD at Johns Hopkins University.

Work in the laboratory is focussed on understanding the underlying defect(s) of the nuclear pore complex (NPC) and its regulation as a disease initiating event in amyotrophic lateral sclerosis, Alzheimer's disease and other dementias along with the development of therapies to mitigate NPC damage. For the last decade, we have employed human and rodent models to explore the role of the NPC in neurodegeneration pathophysiology. The model systems include a very large population of highly characterized induced pluripotent cell lines for ALS , FTD and AD along with transgenic rodent models of these diseases. Most recently we identified a specific set of nucleoporins that initiate a cascade of NPC failure and have now identified an underlying initiating event, including ESCRT-III pathway and gene therapies to mitigate damage/disease. Projects include:

1) Nuclear Biology in Sporadic Neurodegeneration: to address fundamental questions on implicating nuclear pore complex and nuclear transport in dementia and ALS (Donnelley et al, Neuron, 2013; Zhang et al Nature 2015; Grima et al, Neuron 2017; Eftekharzadeh, Neuron 2018; Zhang et al, Cell, 2018, Coyne et al, Neuron 2020) and other related neurodegenerative diseases. We have a library of nucleoporin coding variants we hypothesize are actual disease initiators in ALS and FTD. This project will use CRISPR edited patient lines and ALS/FTD iPS cell lines with defined nucleoporin coding variants to determine if these actually serve as disease initiators- providing the first real evidence of what starts disease in ALS or FTD in sporadic patients. The project involves close collaborations with teams responsible for the assembly of the human nuclear pore complex.

2) Development of therapies targeting the regulation of nuclear pore, nuclear transport and TDP-43 loss of function in neurodegeneration. These studies may involve collaboration with biotechnology companies interested in this new therapeutic target and its potential widespread disease engagement.

3) Development of new iPS and rodent transgenic models of nuclear pore and nuclear pore regulation defects present in familial and sporadic ALS/dementia.

Experimental approaches, including biochemistry, genetics, molecular imaging and cell biology, from human and in vivo/in vitro rodent to mammalian systems are employed. New techniques applied in the lab include iPSC, genome editing, single cell analysis, whole genome analytics and metabolic studies. Access to the largest library of human iPS cell lines (~750) for ALS and dementia along with full omics data thru our ANSWER ALS Program (https://dataportal.answerals.org/home). Candidates with a strong background in molecular biology, advanced imaging (confocal, structured illumination microscopy/Cryo EM), cellular biology, and/or biochemistry are encouraged to apply.

Selected Recent Relevant Publications:

• Coyne et al. Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS. Science Trans Med, 2021.
• Coyne AN, et al. G4C2 Repeat RNA Initiates a POM121-Mediated Reduction in Specific Nucleoporins in C9orf72 ALS/FTD. Neuron. 2020;107(6):1124-40
• Eftekharzadeh B, et al. Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease. Neuron. 2019;101(2):349.:
• Zhang K. Stress granule formation disrupts nucleocytoplasmic transport. 2018;173(4):958-71
• Zhang K et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015;525(7567):56-61.

Position Information: Candidates should have a doctoral degree and strong research background. Please send a statement of research experience and career goals, a copy of Curriculum Vitae, and contact information of at least one or two references to Dr. Jeffrey D. Rothstein (see Contact Information). The post doc position is for at least 2 years or more and is fully funded. Candidates can start at any time.

The Johns Hopkins Medical Institutions provide a stimulating and collaborative environment for biomedical research. Our lab is located in the Brain Science Institute and affiliated with the Depts of Neurology and Neuroscience at the School of Medicine. The Baltimore/Washington D.C. area also offers rich professional and living (county hiking and water activities) opportunities