Initial impact is early in neurodevelopment
Neurodevelopmental origins of SPG11 HSP are evident early in the life of people with the disease and, over time, this gives rise to neurodegeneration.
In normal function, the SPG11 protein, Spatacsin, is important in neurodevelopment and neurodegeneration through its role in the lipid clearance process along with properly functioning lysosomes.
SPG11 is the most common type of complicated autosomal recessive HSP accounting for around 20% of cases.
Hereditary spastic paraplegia (HSP) is a heterogeneous group of rare motor neuron disorders characterized by progressive weakness and spasticity of the lower limbs. HSP type 11 (SPG11-HSP) is linked to pathogenic variants in the SPG11 gene and it represents the most frequent form of complex autosomal recessive HSP.
The majority of SPG11-HSP patients exhibit additional neurological symptoms such as cognitive decline, thin corpus callosum, and peripheral neuropathy. Yet, the mechanisms of SPG11-linked spectrum diseases are largely unknown. Recent findings indicate that spatacsin, the 280 kDa protein encoded by SPG11, may impact the autophagy-lysosomal machinery.
In this update, we summarize the current knowledge of SPG11-HSP. In addition to clinical symptoms and differential diagnosis, our work aims to link the different clinical manifestations with the respective structural abnormalities and cellular in vitro phenotypes. Moreover, we describe the impact of localization and function of spatacsin in different neuronal systems. Ultimately, we propose a model in which spatacsin bridges between neurodevelopmental and neurodegenerative phenotypes of SPG11-linked disorders.
SOURCE: Brain. 2020 May 1;awaa099. doi: 10.1093/brain/awaa099. Online ahead of print. © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. PMID: 32355960
Janus-faced Spatacsin (SPG11): Involvement in Neurodevelopment and Multisystem Neurodegeneration
Tatyana Pozner 1, Martin Regensburger 1 2 3, Tobias Engelhorn 4, Jürgen Winkler 3, Beate Winner 1 5
1 Department of Stem Cell Biology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany.
2 Department of Neurology, FAU Erlangen-Nürnberg, Erlangen, Germany.
3 Department of Molecular Neurology, FAU Erlangen-Nürnberg, Erlangen, Germany.
4 Department of Neuroradiology, FAU Erlangen-Nürnberg, Erlangen, Germany.
5 Center of Rare Diseases Erlangen (ZSEER), FAU Erlangen-Nürnberg, Erlangen, Germany.