Postdoctoral Researcher in axon pathology in ALS

Do you want to contribute to understanding the pathogenesis of the lethal disease ALS?

We are looking for a highly motivated postdoctoral researcher to participate on studies aiming to mechanistically dissect the pathological events leading to motor axon pathology in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). The postdoc project will be conducted in Dr. Eva Hedlund’s research group with the organizational affiliation to Department of Cell and Molecular Biology.

During the past decade we have combined pluripotent stem cells, human tissues and mouse models with advanced RNA sequencing methods to elucidate mechanisms of neuronal vulnerability and resilience in motor neuron diseases, with a focus on ALS and spinal muscular atrophy (SMA). We have identified multiple mechanisms which render certain neurons resilient and which can be modulated in vulnerable neurons to make them less prone to degeneration (Allodi et al, Scientific Reports, 2016, Nichterwitz et al, Nature Communications, 2016; Nijssen et al, Stem Cell Reports, 2018; Nizzardo et al, Acta Neuropathologica, 2020, Nichterwitz, Genome Research, 2020).

With the current project we aim to mechanistically unravel how distinct ALS-causative mutations cause early motor axon pathology using induced pluripotent stem cells (iPSCs) and their derivation to distinct motor neuron subpopulations to model disease, CRISPR/Cas9 genome editing and Axon-RNA sequencing (Axon-seq).

The project

Motor neurons follow a distinct ‘dying-back’ pattern in ALS with the neuromuscular junction (NMJ) and distal axon being early pathological targets. The mechanisms governing this process are largely unknown, but we hypothesize that these are in part due to an early dysregulation in the motor axon transcriptome, destabilising the NMJ. In this project, we aim to study how the human motor axon transcriptome is dysregulated in ALS across mutations and in sporadic disease. We will also functionally evaluate identified transcripts for their role(s) in axonal maintenance and NMJ stability. Towards this goal we have developed an efficient RNA sequencing method for axons, Axon-seq, where motor neurons are grown in microfluidic devices to isolate axons, coupled with Smart-seq RNA sequencing. Additional experimental systems and approaches expected to be used in the project include induced pluripotent stem cells (iPSCs) and their derivation to distinct motor neuron subpopulations to model disease, CRISPR/Cas9 genome editing, viral vectors to modulate gene expression, single cell RNA sequencing and bioinformatics, and high-resolution microscopy techniques. Candidates with a deep interest in ALS neuropathology and skills in molecular and cell biology are strongly encouraged to apply.

In this project, we aim to address the following questions:

(1) Do iPSC-derived motor neurons harboring ALS-causative mutations show unique RNA dysregulation in somas and axons?
(2) Do different ALS-causative mutations cause unique dysregulation of the transcriptome or do they result in common misregulation?
(3) Can axon pathologies in ALS be functionally linked to dysregulation of axonal RNA composition?

The tasks associated with the project will be carried out in a stimulating and collaborative environment with a group of motivated co-workers with both experimental and computational competencies.

Your profile

Qualified to be employed as a postdoctor is one who has obtained a doctorate or has equivalent scientific competence. It is considered as an advantage if you have completed your doctoral degree within the last three years, if there are special reasons, your degree may have been completed earlier. Applicants who have not completed a doctorate at the end of the application period may also apply, provided that all requirements for a completed degree are met before the (intended) date of employment. This must be substantiated by the applicant's main supervisor, director or equivalent.

We are looking for a highly motivated candidate with a strong research background and the following required skills:

Good track record within neurodegenerative disease work
Good track record working with human stem cell culture systems
Experience with RNA sequencing is a strength.
Good interpersonal skills and the ability to work both independently but also as a part of a large team.
Knowledge of relevant biological areas (ALS, motor neurons, stem cells, RNA sequencing)
Knowledge of both spoken and written English and good communication skills.

What do we offer?

Karolinska Institutet is one of the world's leading medical universities. Our vision is to pursue the development of knowledge about life and to promote better health for all. At Karolinska Institutet, we conduct innovative medical research and provide the largest range of biomedical education in Sweden. Karolinska Institutet is a state university, which entitles employees to several benefits such as extended holiday and a generous occupational pension. Employees also have free access to our modern gym and receive reimbursements for medical care.

Location: Solna

Application

An employment application must contain the following documents in English or Swedish:

A complete resumé, including date of the thesis defence, title of the thesis, previous academic positions, academic title, current position, academic distinctions, and committee work
A complete list of publications
A summary of current work (no more than one page)

The application is to be submitted through the Varbi recruitment system.

This position is a 1 year employment.

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