Sandrine Da Cruz lab

Research focus

RNA-binding proteins spreading in ALS
Neurodegenerative diseases are characterised by misfolded, fibrillary aggregated forms of disease-related proteins. These aggregated forms self-propagate and spread throughout the nervous system, suggesting that cell-to-cell transmission of pathological proteins contributes to disease progression. However, to date the underlying mechanisms are not established.
RNA binding proteins have emerged as central players in the mechanisms of neurotoxicity underlying many of the most prominent neurodegenerative diseases. In particular, mutations in TDP-43 and FUS cause ALS and frontotemporal dementia (FTD), and are major protein components of pathological inclusions in most ALS cases and half of FTD instances. We study whether and how de-mixing/aggregation of these disease-causing proteins contributes to neurodegeneration, including by spreading within the central nervous system and/or periphery, and if so which cell types and misfolded species drive disease initiation and progression. 
 
To characterize the relative contribution of neurons and glial cells in FUS spreading, we use co-cultures of hippocampal, cortical or motor neurons and glial cells isolated from humanized FUS mice. We also characterize the structural and biochemical properties of FUS aggregates from patient samples and from ALS-linked FUS mutant proteins. This provides important insights into mechanisms of cell-to-cell spreading which may underlie the source of diversity and cell vulnerability in FUS proteinopathies. 

The role of local axonal translation in neurodegeneration in ALS and FTD 
How local translation is achieved in motor neurons and what role it plays in axonal maintenance and neurodegeneration remains poorly understood. Our work demonstrated that human ALS/FTD-linked mutations in FUS suppress local intra-axonal translation by activation of the integrated stress response which was accompanied by synaptic dysfunction (Lopez-Erauskin et al., Neuron, 2018). 
 
Using a multi-pronged approach integrating microfluidic compartmented chambers, sophisticated mouse models of familial ALS/FTD, and an innovative miniaturized platform modeling functional neuromuscular junctions by co-culturing human motor neurons from patient-derived induced pluripotent stem cells (iPSCs) with muscle cells, we investigate the role of ALS/FTD associated RNA binding proteins [including FUS and TDP-43 - whose aggregation is a hallmark of most ALS and half of the FTD forms] in local translation of mature axons and at neuromuscular junctions. This provides critical insight in the fundamental mechanisms governing local axonal translation and how their perturbation contributes to disease.

Muscle innervation and the development of new therapeutic targets to treat neuromuscular disorders including ALS 
Motor neurons in the central nervous system signal to muscles through sophisticated structures called neuromuscular junctions (NMJs). These connections are critical for motor neurons to induce contractions of muscles that regulate some of our most basic functions, including walking and breathing. One of the earliest events in ALS is the disruption of the NMJs, leading to muscle paralysis and ultimately the death of patients. 

We want to identify small molecules that stimulate (re)innervation or prevent/inhibit NMJ loss in ALS, and ultimately to elucidate key players in NMJ (re)innervation. We modulate the expression of candidate genes to identify new components of NMJ maintenance and want to screen collections of small molecules, including FDA-approved drugs and compounds currently being tested in ALS clinical trials. To this end we exploit an automated co-culture system established by the team, in which motor neurons from mice or human iPSCs establish functional connections with muscle cells, thus allowing to test the potential of therapeutic compounds to reverse disease relevant changes in muscle innervation.
This approach has the potential not only to enable development of therapeutic strategies targeting muscle innervation in ALS or other neuromuscular disorders, but also lead to the elucidation of key molecular components that modulate NMJ innervation and denervation. 

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Job openings

News

International top talents join Leuven neuroscience research community

23/08/2019 - ​The VIB-KU Leuven Center for Brain & Disease Research has attracted two new faculty members. Sandrine Da Cruz will lead a laboratory focusing on the mechanisms of ALS, Lynette Lim will lead a group focusing on the development of neuronal circuits.

Sandrine Da Cruz

Sandrine Da Cruz

Research area(s)

Model organism(s)

Bio

PhD: University of Geneva, Switzerland, 2005
Post-doc: Ludwig Institute for Cancer Research-University of California San Diego (UCSD), US, 2006-2012
Research Scientist: Ludwig Cancer Research San Diego Branch, US, 2013-2015
Assistant Investigator: Ludwig Cancer Research San Diego Branch, US, 2016-present
VIB Group Leader as of October 1, 2019

Contact Info

VIB-KU Leuven Center for Brain & Disease ResearchO&N 4, 6e verdCampus GasthuisbergHerestraat 49, bus 602 3000 LEUVENRoute description