Loss of IVNS1ABP, a gigaxonin paralogue, leads to a progeroid neuropathy due to impaired proteostasis

Bonnard, C., Ali, A. N., Yuan, F., Tan, K. Y., Lim, Y. T., Chan, P. W., Ramanathan, N., Mohamad Kamsani, N. A. B., Chaganty, V., Xiong, D., Tan, Y. S., Chou, S.-M., Chourabi, M., Narayanan, G., Ng, A. Y. J., Tohari, S., Yang, M. W., Karaman, B., Turgut, G. T., Szenker-Ravi, E., Sobota, R., Chen, Z., Bullock, A., Tathallah, R., Altunoglu, U., Byrappa, V., Mathuru, A. S., Shboul, M., Zhang, S.-C., REVERSADE, B.

Genome Institute of Singapore · medrxiv

Paper

Abstract

Impaired proteostasis can induce protein aggregation which is toxic to neuronal cells, contributing to neurodegeneration and other signs of aging. In this study, we delineate an early-onset progressive neuropathy evoking Giant Axonal Neuropathy 1. The causative gene IVNS1ABP encodes a E3-ubiquitin ligase adaptor which is a close gigaxonin paralogue. Patient-derived fibroblasts, iPSCs, and neural progenitors exhibited hallmarks of protein accumulation and lysosomal dysfunction. Ubiquitome analysis revealed overlapping targets with gigaxonin, including Vimentin and MAP1B. The biallelic correction to the isogenic wildtype state in disease- relevant motor neurons partly rescued cellular vulnerabilities. A newly generated ivns1abpa/b knockout zebrafish model partially recapitulated the human peripheral neuropathy, exhibiting aberrant primary motor neuron axon pathfinding, leading to impaired locomotion. Our findings indicate that IVNS1ABP functions in the same pathway as gigaxonin, ensuring appropriate cellular turnover of critical protein substrates, whose accumulation leads to accelerated aging in discrete cellular lineages.

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Research summary

The paper investigates the role of IVNS1ABP in proteostasis and its implications for neurodegeneration, which are relevant to the aging process. However, while it addresses a mechanism related to aging, it primarily focuses on a specific neuropathy rather than a broader approach to understanding or mitigating the root causes of aging. The findings contribute to the understanding of protein aggregation in neurodegeneration but do not present a significant breakthrough that could broadly influence longevity research.

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