Disease-causing mechanism of SPG15 explored

Links between lysosomes, lipids & nerve function

Structural and functional defects in the lysosomes of SPG15 neurons are found in both cell samples from people with SPG15 and also in an SPG15 mouse. Multiple impairments in the neurons happen in association with lysosomal abnormalities, including lipid accumulation and function of the synapses.


Mimoun Azzouz

Hereditary Spastic Paraplegia type 15 (HSP15) is a neurodegenerative condition caused by the inability to produce SPG15 protein, which leads to lysosomal swelling. However, the link between lysosomal aberrations and neuronal death is poorly explored.

To uncover the functional consequences of lysosomal aberrations in disease pathogenesis, we analyze human dermal fibroblasts from HSP15 patients as well as primary cortical neurons derived from an SPG15 knockout (KO) mouse model.

We find that SPG15 protein loss induces defective anterograde transport, impaired neurite outgrowth, axonal swelling and reduced autophagic flux in association with the onset of lysosomal abnormalities. Additionally, we observe lipid accumulation within the lysosomal compartment, suggesting that distortions in cellular lipid homeostasis are intertwined with lysosomal alterations.

We further demonstrate that SPG15 KO neurons exhibit synaptic dysfunction, accompanied by augmented vulnerability to glutamate-induced excitotoxicity.

Overall, our study establishes an intimate link between lysosomal aberrations, lipid metabolism and electrophysiological impairments, suggesting that lysosomal defects are at the core of multiple neurodegenerative disease processes in HSP15.

SOURCE:  Hum Mol Genet. 2022 Mar 21;ddac063. doi: 10.1093/hmg/ddac063. Online ahead of print. PMID: 35313342 © The Author(s) 2022. Published by Oxford University Press.

SPG15 protein deficits are at the crossroads between lysosomal abnormalities, altered lipid metabolism and synaptic dysfunction

Lara Marrone  1   2 Paolo M Marchi  1 Christopher P Webster  1 Raffaele Marroccella  1 Ian Coldicott  1 Steven Reynolds  3 João Alves-Cruzeiro  1 Zih-Liang Yang  1 Adrian Higginbottom  1 Mukhran Khundadze  4 Pamela J Shaw  1 Christian A Hübner  4 Matthew R Livesey  1 Mimoun Azzouz  1

1. Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience, University of Sheffield, Sheffield, UK.

2. Currently at Janssen Pharmaceutica, Department of Neuroscience, Beerse, Belgium.

3. Academic Unit of Radiology, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK.

4. Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.

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