Neurodegeneration beyond the brain: Tales of cell death, nuclear pores and stem cells

Karyoptosis is a newly discovered cell death mechanism, where nuclear membrane integrity progressively declines in response to impairment of autophagy. It has been identified that the nuclear lamina protein LaminB1 is integral in this process, whereby nuclear degradation occurs when LaminB1 is phosphorylated by the stress kinase p38 MAPK. During my PhD I used several experimental systems to explore details of karyoptosis as a mechanism for the first time. In particular, I examined whether karyoptosis is triggered by any of the toxic dipeptide repeat proteins (DPRs) produced by a repeat expansion mutation in the C9ORF72 gene which causes ALS/FTD. As a post-doc I am now exploring what links the nuclear lamina might have with TDP-43 pathology and dysfunctional DNA repair mechanisms in ALS/FTD.

Amyotrophic lateral sclerosis (ALS) is characteristically heterogenous, with multiple genes contributing to disease onset. To better represent the broad genetic landscape of ALS, the availability and variety of cellular models can be increased. To this end, I have been involved in the generation of over 40 patient-derived and isogenic induced pluripotent stem cell (iPSC) lines for ALS disease modelling. Throughout my PhD, which I completed part-time, and in my current post-doctoral role, I have utilised these novel iPSC lines for neuronal profiling across multiple genetic forms of ALS. This talk will highlight the organisation of iPSC-based research to improve data-reliability and time-efficiency, alongside examples of neuronal characterisation with an emphasis on imaging techniques.

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are debilitating neurodegenerative conditions forming a clinical continuum. These diseases share a genetic trigger, the C9orf72 repeat expansion and are thus referred to as C9ALS/FTD. Central to the pathogenesis of C9ALS/FTD is the dual process of nuclear loss and cytoplasmic aggregation of TDP-43. Additionally, nucleocytoplasmic transport is compromised. However, the precise link connecting disruptions in nuclear transport with nuclear depletion of TDP-43 and its aberrant accumulation in the cytoplasm remains enigmatic. My research explores the role of nuclear pore dysfunction in the context of C9ALS/FTD and our new findings provide a compelling rationale for the selective mislocalization of TDP-43 in these devastating conditions.