Tsintzas, E. | Search bioRxiv

bioRxiv2023

Differential neuronal vulnerability to C9orf72 repeat expansion driven by Xbp1 transcription signature

A G4C2 repeat expansion in the gene C9orf72 (C9) is the most common genetic cause of sporadic and familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). What determines why cell death is triggered only in specific neuronal populations, while others remain protected or are less susceptible to disease is still an open question. In particular, whether it is the transcriptional response to the accumulation of toxic insults or the initial cellular state that determines their vulnerability is still unknown. We have carried out a large-scale profiling of single cell transcriptional signatures throughout disease development in a Drosophila model of C9 repeat toxicity. This enabled us to monitor transcriptional shifts and track changes in cell populations during disease progression. We have identified neuronal populations which are depleted in response to C9 repeat expression, and therefore vulnerable to toxicity. On the other hand, other neuron types are resistant to toxicity, and maintain their cell number during disease progression. Our findings suggest that a major determinant of vulnerability is the transcriptional state of the cell before it is exposed to C9 repeat expression. We have identified a conserved transcriptional profile that is associated with resistance to C9 repeat toxicity. Neurons resistant to disease display a higher expression of genes involved in protein homeostasis, with Xbp1 identified as a crucial transcription factor determining neuronal vulnerability.

neuroscience↗

bioRxiv2023

A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models

Brains are highly metabolically active organs, consuming 20% of an organisms energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, its unclear if the two are linked. Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested. Here, we find that increasing pyruvate import in Drosophila neurons by over-expression of the transporter bumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimers disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.

neuroscience↗