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Genetic diversity of axon degenerative mechanisms in models of Parkinson's disease

Peters, Owen M., Weiss, Alexandra, Metterville, Jake, Song, Lina, Logan, Robert, Smith, Gaynor A., Schwarzschild, Michael A., Mueller, Christian, Brown, Robert H. and Freeman, Marc 2021. Genetic diversity of axon degenerative mechanisms in models of Parkinson's disease. Neurobiology of Disease 155 , 105368. 10.1016/j.nbd.2021.105368

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Abstract

Parkinson's disease (PD) is the most common form of neurodegenerative movement disorder, associated with profound loss of dopaminergic neurons from the basal ganglia. Though loss of dopaminergic neuron cell bodies from the substantia nigra pars compacta is a well-studied feature, atrophy and loss of their axons within the nigrostriatal tract is also emerging as an early event in disease progression. Genes that drive the Wallerian degeneration, like Sterile alpha and toll/interleukin-1 receptor motif containing (Sarm1), are excellent candidates for driving this axon degeneration, given similarities in the morphology of axon degeneration after axotomy and in PD. In the present study we assessed whether Sarm1 contributes to loss of dopaminergic projections in mouse models of PD. In Sarm1 deficient mice, we observed a significant delay in the degeneration of severed dopaminergic axons distal to a 6-OHDA lesion of the medial forebrain bundle (MFB) in the nigrostriatal tract, and an accompanying rescue of morphological, biochemical and behavioural phenotypes. However, we observed no difference compared to controls when striatal terminals were lesioned with 6-OHDA to induce a dying back form of neurodegeneration. Likewise, when PD phenotypes were induced using AAV-induced alpha-synuclein overexpression, we observed similar modest loss of dopaminergic terminals in Sarm1 knockouts and controls. Our data argues that axon degeneration after MFB lesion is Sarm1-dependent, but that other models for PD do not require Sarm1, or that Sarm1 acts with other redundant genetic pathways. This work adds to a growing body of evidence indicating Sarm1 contributes to some, but not all types of neurodegeneration, and supports the notion that while axon degeneration in many context appears morphologically similar, a diversity of axon degeneration programs exist.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Publisher: Elsevier
ISSN: 0969-9961
Date of First Compliant Deposit: 17 May 2021
Date of Acceptance: 18 April 2021
Last Modified: 21 May 2021 13:35
URI: http://orca.cardiff.ac.uk/id/eprint/141383

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