Mechanisms regulating neurodegeneration and repair

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

Investigators

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Abstract

Most neurodegenerative diseases stem from complex and poorly understood combinations of genetic and environmental causes. One of the biggest challenges in treating these disorders is the wide range of etiologies they arise from. Therefore, an effective strategy would be to block degeneration downstream of the confluence of causes by targeting pathways that are shared across diseases. A critical pathway controlling neurodegeneration involves the dual leucine zipper kinase (DLK; MAP3K12) signaling pathway. DLK is a MAP triple kinase that acts as an injury sensor in neurons and when activated leads to axon degeneration and neuronal death. The canonical DLK pathway signals via a retrograde kinase cascade involving JNK (cJun N terminal kinase) to activate a transcriptional switch in the nucleus that is thought to lead to the major downstream consequences, including cell death. Key open questions surrounding DLK function include how it is activated and by what exact mechanisms it drives retrograde signaling. It is important to recognize that in addition to DLK, other cellular pathways promote and cause neurodegeneration, many of which remain unknown. A long-term aim is to uncover more of them. This year, we have made the following progress: First, we have uncovered an entirely distinct axonal signaling pathway under control of DLK that does not depend on transcription. Using laser axotomy of human iPSC-derived neurons, we showed that after an injury, DLK drives a local mitochondrial fission cascade in the axon via activation of dynamin related peptide 1 (DRP1), causing retrograde axon degeneration and eventual neuronal apoptosis (Gomez-Deza et al, Biorxiv 2023). Secondly, we extended my previous work that showed DLK was a powerful driver of motor neuron (MN) death in the SOD1G93A mouse model of ALS. We reasoned that blocking DLK protects MNs from dying but likely blunts the regenerative capacity of the MNs since DLK is also upstream of an adaptive response in neurons with regenerative ability. Therefore, we combined DLK deletion with the expression of a pro-regenerative transgene (Thy1-ATF3), hypothesizing that neurons expressing this combination might be more potently protected in this mouse model. We found that in SOD1G93A mice with DLK deletion and ATF3 expression, motor neuron function was powerfully preserved into late stages of disease (Wlaschin et al., 2023). This study highlights the importance of combinatorial therapies for the treatment of neurodegenerative disorders. Equally importantly, our study exposes the need to gain a more detailed understanding of the individual cells affected in ALS. With this in mind, as a first step, we have turned to single cell transcriptomics to molecularly identify different MN cell types both in mouse and in man (Alkaslasi et al., 2021; Yadav et al. 2023).