Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy
Open accessAbstract
Mutations of FIG4 are responsible for Yunis-Varón syndrome, familial epilepsy with polymicrogyria, and Charcot-Marie-Tooth type 4J neuropathy (CMT4J). Although loss of the FIG4 phospholipid phosphatase consistently causes decreased PtdIns(3,5)P₂ levels, cell-specific sensitivity to partial loss of FIG4 function may differentiate FIG4-associated disorders. CMT4J is an autosomal recessive neuropathy characterized by severe demyelination and axonal loss in human, with both motor and sensory involvement. However, it is unclear whether FIG4 has cell autonomous roles in both motor neurons and Schwann cells, and how loss of FIG4/PtdIns(3,5)P₂-mediated functions contribute to the pathogenesis of CMT4J. Here, we report that mice with conditional inactivation of Fig4 in motor neurons display neuronal and axonal degeneration. In contrast, conditional inactivation of Fig4 in Schwann cells causes demyelination and defects in autophagy-mediated degradation. Moreover, Fig4-regulated endolysosomal trafficking in Schwann cells is essential for myelin biogenesis during development and for proper regeneration/remyelination after injury. Our data suggest that impaired endolysosomal trafficking in both motor neurons and Schwann cells contributes to CMT4J neuropathy.
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SNCA accumulation over time might impair autophagy function.
“SNCA accumulation over time might impair autophagy function”
From Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). (2016) · cites this paper as [1749]
The Results and Discussion passages describe impaired autophagy after Fig4 loss and the subsequent accumulation of ubiquitinated proteins in Schwann cells. Searches for SNCA and alpha-synuclein found no passage addressing whether their accumulation impairs autophagy; the reported relationship concerns different proteins and runs in the other direction. (LLM, conf=0.75)
Experimental — accuracy not yet measuredAutophagy is regulated by distinct mechanisms in different cell types, and these cell type-specific mechanisms underlie the differential vulnerability of separate tissues to autophagy mutations, resulting in heterogeneous manifestations of disease.
“Furthermore, mounting evidence shows that autophagy is regulated by distinct mechanisms in different cell types [11–26], and these cell type-specific mechanisms underlie the differential vulnerability of separate tissues to autophagy mutations, resulting in heterogenous manifestations of disease.”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [13]
In CMT4J, autosomal recessive mutations in FIG4 lead to incompetent myelinophagy.
“In CMT4J, autosomal recessive mutations in the gene encoding FIG4, a phosphatase required for recycling phosphoinositides involved in vesicle trafficking, lead to incompetent myelinophagy [13].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [13]
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Background
- Authors
- Vaccari, I., Carbone, A., Previtali, S. C., Mironova, Y. A., Alberizzi, V., Noseda, R., Rivellini, C., Bianchi, F., Del Carro, U., D'Antonio, M., Lenk, G. M., Wrabetz, L., Giger, R. J., Meisler, M. H., & Bolino, A.
- Affiliations
- University of Michigan (US)
- University at Buffalo, State University of New York (US)
- Corresponding author
- Bolino, Alessandra
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-09-03
- Volume
- 24
- Issue
- 2
- Pages
- 383-396
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC4275070
- OpenAlex
- W2165355490
- Cited by
- 49
- References
- 49
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 3 · 2022: 1 · 2021: 8 · 2020: 5 · 2019: 7 · 2018: 6 · 2017: 2 · 2016: 6 · 2015: 4 · 2014: 1
- FWCI
- 1.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Human Molecular Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion, cc-by)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Funders
- E-Rare (JTC2011)
- National Institute of General Medical Sciences (R01GM024872, R01-GM24872, T32GM007315)
- National Institute of Neurological Disorders and Stroke (R01NS081281)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007505)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- FIG4, Schwann cells, motor neurons, phosphatidylinositol 3,5-bisphosphate, demyelination, axonal degeneration, autophagy, endolysosomal trafficking, myelin biogenesis, remyelination, conditional knockout, neuropathy pathogenesis
- MeSH terms
- Phosphoinositide Phosphatases, Animals, Charcot-Marie-Tooth Disease, Flavoproteins, Humans, Mice, Inbred C57BL, Motor Neurons, Myelin Sheath, Phosphatidylinositols, Endosomes, Schwann Cells, Gene Silencing, Protein Transport, Mice
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