Journal article
Proteomic analysis reveals early pathological defects in corticospinal motor neurons of a spastin model of hereditary spastic paraplegia, which are improved by NU-9 treatment
Neurobiology of disease, v 227, 107494
19 Jun 2026
PMID: 42320547
Abstract
Upper motor neuron (UMN) degeneration is a characteristic feature of hereditary spastic paraplegia (HSP), a genetically heterogeneous heritable neurodegenerative disorder resulting from mutations in over ninety genes. The mutations in the SPAST gene, which encodes the microtubule-severing protein spastin, are responsible for about 40% of all HSP cases. To date, the cellular and molecular mechanisms linking mutant spastin protein to UMN vulnerability in HSP patients remain unknown and there are no disease modifying therapies. To address this knowledge gap, we isolated pure populations of corticospinal motor neurons (CSMN; a.k.a. UMN in mice) from SPAST
-UeGFP reporter mice at two pre-symptomatic time points and performed bottom-up proteomic analyses to reveal changes in their proteome that informs the underlying causes of their initial vulnerability. We find dynamic changes in their proteome and that limitations with cytoarchitectural integrity and stability of key organelles contribute to their neuronal vulnerability. Since the compound NU-9 was shown to improve similar cellular problems in CSMN that are diseased due to misfolded SOD1 toxicity and TDP-43 pathology, we further investigated its effect on the well-established pathological features of HSP that are recapitulated in the SPAST
mice. We find that NU-9 treatment (100 mg/kg, for 100 days) significantly prevented degeneration of corticospinal axons, restored the integrity of mitochondria and endoplasmic reticulum, and reduced the presence of electron-dense accumulations in the CSMN of SPAST
mice.
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Details
- Title
- Proteomic analysis reveals early pathological defects in corticospinal motor neurons of a spastin model of hereditary spastic paraplegia, which are improved by NU-9 treatment
- Creators
- Mukesh Gautam - Northwestern UniversityMercedes Priego - University of Illinois ChicagoChristopher Quintanilla - Northwestern UniversityOmar Kashow - Northwestern UniversityByoung-Kyu Cho - Washington University in St. LouisYoung Ah Goo - Washington University in St. LouisRichard B Silverman - Northwestern UniversityGerardo Morfini - University of Illinois ChicagoPeter W Baas - Drexel UniversityP Hande Ozdinler (Corresponding Author) - Northwestern University
- Publication Details
- Neurobiology of disease, v 227, 107494
- Publisher
- Elsevier
- Number of pages
- 13
- Grant note
- NIH: R21 NIH-NIA: R01 AG061708 Spastic Paraplegia Foundation Cure SPG4 Foundation A Long Swim and Queen B Foundation
This work has been funded by NIH-R21 (P.HO), NIH-NIA R01 AG061708 (P.H.O and R.B.S), Spastic Paraplegia Foundation (P.H.O), Cure SPG4 Foundation (P.H.O), and A Long Swim and Queen B Foundation (P.H.O and M.G). We thank Dr. Emel Ulupinar for helping with microdissection prior to FACS purification. We thank Dr. Baris Genc and Richard M. Wollf with statistical analyses. We thank the Center for Flowcytometry at Northwestern for their help and guidance during FACS purification. We thank Dr. Baris Genc for helping with figure preparation.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Web of Science ID
- WOS:001807034600001
- Other Identifier
- 991022192997604721