Comparative Proteomic Profiling Reveals Mechanisms for Early Spinal Cord Vulnerability in CLN1 Disease

Overview

Journal Sci Rep

Specialty Science

Date 2020 Sep 17

PMID 32938982

Citations 7

Authors

Hemanth R Nelvagal

Maica Llavero Hurtado

Samantha L Eaton

Rachel A Kline

Douglas J Lamont

Mark S Sands

Thomas M Wishart

Jonathan D Cooper

Affiliations

Soon will be listed here.

Abstract

CLN1 disease is a fatal inherited neurodegenerative lysosomal storage disease of early childhood, caused by mutations in the CLN1 gene, which encodes the enzyme Palmitoyl protein thioesterase-1 (PPT-1). We recently found significant spinal pathology in Ppt1-deficient (Ppt1) mice and human CLN1 disease that contributes to clinical outcome and precedes the onset of brain pathology. Here, we quantified this spinal pathology at 3 and 7 months of age revealing significant and progressive glial activation and vulnerability of spinal interneurons. Tandem mass tagged proteomic analysis of the spinal cord of Ppt1and control mice at these timepoints revealed a significant neuroimmune response and changes in mitochondrial function, cell-signalling pathways and developmental processes. Comparing proteomic changes in the spinal cord and cortex at 3 months revealed many similarly affected processes, except the inflammatory response. These proteomic and pathological data from this largely unexplored region of the CNS may help explain the limited success of previous brain-directed therapies. These data also fundamentally change our understanding of the progressive, site-specific nature of CLN1 disease pathogenesis, and highlight the importance of the neuroimmune response. This should greatly impact our approach to the timing and targeting of future therapeutic trials for this and similar disorders.

Citing Articles

Subacute and chronic proteomic and phosphoproteomic analyses of a mouse model of traumatic brain injury at two timepoints and comparison with chronic traumatic encephalopathy in human samples.

Morin A, Davis R, Darcey T, Mullan M, Mouzon B, Crawford F Mol Brain. 2022; 15(1):62.

PMID: 35850691 PMC: 9290256. DOI: 10.1186/s13041-022-00945-4.

Effects of chronic cannabidiol in a mouse model of naturally occurring neuroinflammation, neurodegeneration, and spontaneous seizures.

Dearborn J, Nelvagal H, Rensing N, Takahashi K, Hughes S, Wishart T Sci Rep. 2022; 12(1):11286.

PMID: 35789177 PMC: 9253004. DOI: 10.1038/s41598-022-15134-5.

Glial Dysfunction and Its Contribution to the Pathogenesis of the Neuronal Ceroid Lipofuscinoses.

Takahashi K, Nelvagal H, Lange J, Cooper J Front Neurol. 2022; 13:886567.

PMID: 35444603 PMC: 9013902. DOI: 10.3389/fneur.2022.886567.

Identification of substrates of palmitoyl protein thioesterase 1 highlights roles of depalmitoylation in disulfide bond formation and synaptic function.

Gorenberg E, Tieze S, Yucel B, Zhao H, Chou V, Wirak G PLoS Biol. 2022; 20(3):e3001590.

PMID: 35358180 PMC: 9004782. DOI: 10.1371/journal.pbio.3001590.

Isolation of Transcriptomic-Quality Total RNA from Mouse Spinal Cords.

Stokes J, Nicaise A, Frodella C, Varela-Stokes A, Thompson T, Kaplan B Curr Protoc. 2022; 2(1):e338.

PMID: 35030295 PMC: 8852305. DOI: 10.1002/cpz1.338.

References

Mole S, Anderson G, Band H, Berkovic S, Cooper J, Kleine Holthaus S . Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis. Lancet Neurol. 2018; 18(1):107-116. DOI: 10.1016/S1474-4422(18)30368-5. View

Kohlschutter A, Schulz A, Bartsch U, Storch S . Current and Emerging Treatment Strategies for Neuronal Ceroid Lipofuscinoses. CNS Drugs. 2019; 33(4):315-325. PMC: 6440934. DOI: 10.1007/s40263-019-00620-8. View

Mukherjee A, Appu A, Sadhukhan T, Casey S, Mondal A, Zhang Z . Emerging new roles of the lysosome and neuronal ceroid lipofuscinoses. Mol Neurodegener. 2019; 14(1):4. PMC: 6335712. DOI: 10.1186/s13024-018-0300-6. View

Vesa J, Hellsten E, Verkruyse L, Camp L, Rapola J, Santavuori P . Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Nature. 1995; 376(6541):584-7. DOI: 10.1038/376584a0. View

PASTRAKULJIC N . [Fibrinogen in diseases of the liver and its effect on the development of hemorrhage]. Srp Arh Celok Lek. 1983; 111(9-10):1317-23. View

Galvin N, Vogler C, Levy B, Kovacs A, Griffey M, Sands M . A murine model of infantile neuronal ceroid lipofuscinosis-ultrastructural evaluation of storage in the central nervous system and viscera. Pediatr Dev Pathol. 2007; 11(3):185-92. PMC: 2789460. DOI: 10.2350/07-03-0242.1. View

Staropoli J, Haliw L, Biswas S, Garrett L, Holter S, Becker L . Large-scale phenotyping of an accurate genetic mouse model of JNCL identifies novel early pathology outside the central nervous system. PLoS One. 2012; 7(6):e38310. PMC: 3368842. DOI: 10.1371/journal.pone.0038310. View

Shyng C, Nelvagal H, Dearborn J, Tyynela J, Schmidt R, Sands M . Synergistic effects of treating the spinal cord and brain in CLN1 disease. Proc Natl Acad Sci U S A. 2017; 114(29):E5920-E5929. PMC: 5530669. DOI: 10.1073/pnas.1701832114. View

Kuhl T, Dihanich S, Wong A, Cooper J . Regional brain atrophy in mouse models of neuronal ceroid lipofuscinosis: a new rostrocaudal perspective. J Child Neurol. 2013; 28(9):1117-22. DOI: 10.1177/0883073813494479. View

10.

Bible E, Gupta P, Hofmann S, Cooper J . Regional and cellular neuropathology in the palmitoyl protein thioesterase-1 null mutant mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis. 2004; 16(2):346-59. DOI: 10.1016/j.nbd.2004.02.010. View

11.

Kielar C, Maddox L, Bible E, Pontikis C, Macauley S, Griffey M . Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis. 2006; 25(1):150-62. PMC: 1866219. DOI: 10.1016/j.nbd.2006.09.001. View

12.

Macauley S, Wozniak D, Kielar C, Tan Y, Cooper J, Sands M . Cerebellar pathology and motor deficits in the palmitoyl protein thioesterase 1-deficient mouse. Exp Neurol. 2009; 217(1):124-35. PMC: 2679857. DOI: 10.1016/j.expneurol.2009.01.022. View

13.

REXED B . A cytoarchitectonic atlas of the spinal cord in the cat. J Comp Neurol. 1954; 100(2):297-379. DOI: 10.1002/cne.901000205. View

14.

Kline R, Dissanayake K, Hurtado M, Martinez N, Ahl A, Mole A . Altered mitochondrial bioenergetics are responsible for the delay in Wallerian degeneration observed in neonatal mice. Neurobiol Dis. 2019; 130:104496. PMC: 6704473. DOI: 10.1016/j.nbd.2019.104496. View

15.

Jones R, Harrison C, Eaton S, Hurtado M, Graham L, Alkhammash L . Cellular and Molecular Anatomy of the Human Neuromuscular Junction. Cell Rep. 2017; 21(9):2348-2356. PMC: 5723673. DOI: 10.1016/j.celrep.2017.11.008. View

16.

Hurtado M, Fuller H, Wong A, Eaton S, Gillingwater T, Pennetta G . Proteomic mapping of differentially vulnerable pre-synaptic populations identifies regulators of neuronal stability in vivo. Sci Rep. 2017; 7(1):12412. PMC: 5622084. DOI: 10.1038/s41598-017-12603-0. View

17.

Mi H, Muruganujan A, Huang X, Ebert D, Mills C, Guo X . Protocol Update for large-scale genome and gene function analysis with the PANTHER classification system (v.14.0). Nat Protoc. 2019; 14(3):703-721. PMC: 6519457. DOI: 10.1038/s41596-019-0128-8. View

18.

Kielar C, Wishart T, Palmer A, Dihanich S, Wong A, Macauley S . Molecular correlates of axonal and synaptic pathology in mouse models of Batten disease. Hum Mol Genet. 2009; 18(21):4066-80. PMC: 2758138. DOI: 10.1093/hmg/ddp355. View

19.

Wishart T, Huang J, Murray L, Lamont D, Mutsaers C, Ross J . SMN deficiency disrupts brain development in a mouse model of severe spinal muscular atrophy. Hum Mol Genet. 2010; 19(21):4216-28. PMC: 2951867. DOI: 10.1093/hmg/ddq340. View

20.

Theocharidis A, van Dongen S, Enright A, Freeman T . Network visualization and analysis of gene expression data using BioLayout Express(3D). Nat Protoc. 2009; 4(10):1535-50. DOI: 10.1038/nprot.2009.177. View