Neurofilament accumulation disrupts autophagy in giant axonal neuropathy

Year: 2025

Type: article

Abstract: Neurofilament accumulation is associated with many neurodegenerative diseases, but it is the primary pathology in giant axonal neuropathy (GAN). This childhood-onset autosomal recessive disease is caused by loss-of-function mutations in gigaxonin, the E3 adaptor protein that enables neurofilament degradation. Using a combination of genetic and RNA interference approaches, we found that dorsal root ganglia from mice lacking gigaxonin have impaired autophagy and lysosomal degradation through 2 mechanisms. First, neurofilament accumulations interfere with the distribution of autophagic organelles, impairing their maturation and fusion with lysosomes. Second, the accumulations attract the chaperone 14-3-3, which is responsible for the proper localization of the key autophagy regulator transcription factor EB (TFEB). We propose that this dual disruption of autophagy contributes to the pathogenesis of other neurodegenerative diseases involving neurofilament accumulations.

Source: JCI Insight

DOI: 10.1172/jci.insight.177999

Authors: Jean-Michel Paumier, James Zewe, Chiranjit Panja, Melissa R. Pergande, Meghana Venkatesan, Eitan Israeli, Shikha Prasad, Natasha Snider, Jeffrey N. Savas, Puneet Opal

Institutions: Northwestern University, University of North Carolina at Chapel Hill

Language: English

Topic: Hereditary Neurological Disorders

Subfield: Cellular and Molecular Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,100

Funders: Muscular Dystrophy Association, Northwestern University, National Institutes of Health, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, National Institute on Aging, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences

OpenAlex ID: W4408264157