Biological Sciences

Events and seminars

Monday Seminar Series - "From Mechanisms of Neurodegeneration towards Therapy Development in Amyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTD)"

Prof Sandrine da Cruz - VIB-KU Leuven Center for Brain & Disease Research

25th March 2024 at 12:05pm [Download iCalendar / .ics file]

Daniel Rutherford, G.27, LT1

The Da Cruz lab focuses on disease mechanisms and therapy development for Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) using mouse models as well as in vitro cellular models including patient-induced pluripotent stem cells. Her lab investigates two main questions: 1) what causes the early demise of neuromuscular junctions (NMJs) in ALS by studying the role of local axonal translation in the maintenance and loss of axons and NMJs and by screening for therapeutics that improve muscle innervation using a miniaturized motor neuron/muscle co-culture platform and (2) how aberrant phase separation/aggregation of RNA binding proteins TDP-43 and FUS causes toxicity in ALS and FTD.

Recently we, and others, uncovered a role of ALS/FTD-causative protein FUS in axonal translation and we demonstrated that ALS/FTD-causing FUS mutations suppress local protein synthesis in adult mouse axons prior to disease symptoms. Together, evidence points to disrupted axonal protein synthesis as a key contributor to axon degeneration and neuromuscular junction (NMJ) loss, one of the earliest events in ALS. However, the underlying mechanisms are still unknown. We propose that local mRNA translation and the specific local compartmentalization of the translation machinery are crucial for the regulation of the mature motor axon and the functioning of NMJs, and that its disruption underlies neurodegeneration.

To shed light into disease-associated axonal targets, we are exploiting our ALS mouse models as well as cellular systems coupled with spatial omics approaches to map the local transcriptomes in lower motor axons and NMJs in the context of inherited forms as well as environmental stressors. The mechanisms driving axonal maintenance and loss are then validating using a wide range of approaches including single-molecule resolution in situ hybridization and super-resolution microscopy.

Together, our work has the potential to further our understanding of how mature axons and their synapses with muscles are lost in ALS and may identify targets for effective therapeutic intervention.

My talk will thus be divided in 3 main parts:

- I will start with a brief introduction on ALS/FTD relevant to the talk

- I will then describe some of our efforts towards deciphering mechanisms underlying axonal/neuromuscular junction degeneration caused by ALS-causing mutations in FUS and TDP-43 using omics approaches with emphasis on the role of local protein translation

- Finally, I will talk about our efforts towards deciphering mechanisms of phase separation, aggregation and spreading of FUS and TDP-43 with a focus on some of the new models we recently built.

Host Dhanya Cheerambathur, ICB

iCalendar / ICS feed

Seminars are available in .ics format utilised by various calendar and email programs including Google Calendar, Apple iCal, and Microsoft Outlook.

RSS Feeds from Biology

Events and seminars are available via an RSS feed. Please click the link below to subscribe.