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PreprintCC BY-NDbioRxiv

Paralemmin-2 is a membrane-anchored cytoskeletal constituent of Axon Initial Segments and nodes of Ranvier

  • V. Macarron-Palacios
  • N. G. Metzendorf
  • G. Hultqvist
  • C. Acuna
  • S. Kneilmann
  • J. Hubrich
  • L. Wüstefeld
  • H. Martens
  • M. W. Kilimann
  • E. D'Este1
  1. 1Max Planck Institute for Medical Research
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Abstract

The axon initial segment (AIS) and nodes of Ranvier (NoR) are essential for action potential initiation and propagation. They share many features of their molecular architecture, and their assembly mechanisms converge on the membrane-associated periodic skeleton (MPS). Here, we identify Paralemmin-2 (Palm2) as a component of both the AIS and NoR. Palm2 depletion shortens the AIS and reduces neuronal excitability. Endogenous Palm2 in the AIS is non-periodic, but upon overexpression it associates with the MPS, localizing to actin rings and reducing {beta}IV-spectrin abundance and periodicity. In NoR of the central and peripheral nervous system, Palm2 localizes to different subdomains - nodal or paranodal, respectively. Palm2, and its homolog Palm1, bind the deubiquitinase USP7, implicating paralemmins in proteostasis at the MPS. The complementary localizations of Palm2 and Palm1 at the AIS/NoR or axon shafts, respectively, parallel the distributions of {beta}-spectrin and ankyrin isoforms between these axonal compartments. We propose that Palm2 modulates the submembrane cytoskeleton and its membrane attachment, and thus contributes to the assembly, functioning and remodeling of the AIS and NoR.

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Cite

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BibTeX
@misc{macarronpalacios2026paralemmin2,
  title = {{Paralemmin-2 is a membrane-anchored cytoskeletal constituent of Axon Initial Segments and nodes of Ranvier}},
  author = {V. Macarron-Palacios and N. G. Metzendorf and G. Hultqvist and C. Acuna and S. Kneilmann and J. Hubrich and L. Wüstefeld and H. Martens and M. W. Kilimann and E. D'Este},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.03.749080},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.03.749080v1},
  note = {CC BY-ND},
}
RIS
TY  - UNPB
TI  - Paralemmin-2 is a membrane-anchored cytoskeletal constituent of Axon Initial Segments and nodes of Ranvier
AU  - V. Macarron-Palacios
AU  - N. G. Metzendorf
AU  - G. Hultqvist
AU  - C. Acuna
AU  - S. Kneilmann
AU  - J. Hubrich
AU  - L. Wüstefeld
AU  - H. Martens
AU  - M. W. Kilimann
AU  - E. D'Este
PY  - 2026
DA  - 2026/09/03
PB  - bioRxiv
DO  - 10.64898/2026.09.03.749080
UR  - https://www.biorxiv.org/content/10.64898/2026.09.03.749080v1
AB  - The axon initial segment (AIS) and nodes of Ranvier (NoR) are essential for action potential initiation and propagation. They share many features of their molecular architecture, and their assembly mechanisms converge on the membrane-associated periodic skeleton (MPS). Here, we identify Paralemmin-2 (Palm2) as a component of both the AIS and NoR. Palm2 depletion shortens the AIS and reduces neuronal excitability. Endogenous Palm2 in the AIS is non-periodic, but upon overexpression it associates with the MPS, localizing to actin rings and reducing {beta}IV-spectrin abundance and periodicity. In NoR of the central and peripheral nervous system, Palm2 localizes to different subdomains - nodal or paranodal, respectively. Palm2, and its homolog Palm1, bind the deubiquitinase USP7, implicating paralemmins in proteostasis at the MPS. The complementary localizations of Palm2 and Palm1 at the AIS/NoR or axon shafts, respectively, parallel the distributions of {beta}-spectrin and ankyrin isoforms between these axonal compartments. We propose that Palm2 modulates the submembrane cytoskeleton and its membrane attachment, and thus contributes to the assembly, functioning and remodeling of the AIS and NoR.
ER  -