New Findings on SPG11 HSP mechanism

Posted - June 2016 in Research Highlights

Potential treatment target identified

 

This German study using induced pluripotent stem cells from 3 SPG11 HSPers has identified an enzyme (glycogen synthase kinase 3 beta) necessary for the normal function of many cell proteins as a potential treatment target for SPG11 HSP.

 

OBJECTIVE:

Mutations in the Spastic Paraplegia Gene11 (SPG11), encoding spatacsin, cause the most frequent form of autosomal recessive (AR) complex hereditary spastic paraplegia (HSP) and juvenile onset amyotrophic lateral sclerosis (ALS5). When SPG11 is mutated, patients frequently present with spastic paraparesis, a thin corpus callosum, and cognitive impairment.

 

We previously delineated a neurodegenerative phenotype in neurons of these patients. In the current study, we recapitulated early developmental phenotypes of SPG11 and outlined their cellular and molecular mechanisms in patient-specific induced pluripotent stem cell (iPSC) derived cortical neural progenitor cells (NPCs).

 

METHODS:

We generated and characterized iPSC derived NPCs and neurons from three SPG11 patients and two age-matched controls.

 

RESULTS:

Gene expression profiling of SPG11-NPCs revealed widespread transcriptional alterations in neurodevelopmental pathways. These include changes in cell cycle, neurogenesis, cortical development pathways, in addition to autophagic deficits. More importantly, the GSK3ß signaling pathway was found to be dysregulated in SPG11-NPCs. Impaired proliferation of SPG11-NPCs resulted in a significant diminution in the number of neural cells. The decrease in mitotically active SPG11-NPCs was rescued by GSK3 modulation.

 

INTERPRETATION:

This iPSC-derived NPC model provides the first evidence for an early neurodevelopmental phenotype in SPG11, with GSK3ß as a potential novel target to reverse the disease phenotype.

 

SOURCE: Ann Neurol. 2016 Mar 11. doi: 10.1002/ana.24633. [Epub ahead of print] © 2016 American Neurological Association. PMID: 26971897 [PubMed – as supplied by publisher]

 

GSK3ß-dependent dysregulation of neurodevelopment in SPG11-patient iPSC model.

 

Mishra HK1, Prots I1, Havlicek S1, Kohl Z2, Perez-Branguli F1, Boerstler T1, Anneser L1, Minakaki G2, Wend H1, Hampl M3, Leone M4, Brückner M5, Klucken J2, Reis A6, Boyer L7, Schuierer G8, Behrens J5, Lampert A3,9, Engel FB4, Gage FH7, Winkler J2, Winner B1.

 

1 IZKF Junior Research Group and BMBF Research Group Neuroscience, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.

2 Department of Molecular Neurology, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.

3 Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.

4 Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.

5 Department of Experimental Medicine, Nikolaus-Fiebiger-Centre for Molecular Medicine, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.

6 Institute of Human Genetics, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.

7 Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.

8 Institute of Neuroradiology, Center of Neuroradiology, Regensburg.

9 Institute of Physiology, RWTH University, Aachen, Germany.

Comments on this story

  1. Carina posted at 8:32 am on 25 August 2016Reply

    Is this good news for Spg11 patients? For a potential treatment and how long will this be before it comes to light?

    • Editor posted at 10:23 am on 25 August 2016Reply

      Editor’s Note: Discovering and understanding disease-causing mechanisms is pre-requisite to establishing effective treatments (except in those rare cases where cures are discovered unintentionally). This study sheds further light on the disease-causing mechanism for SPG11, so in that respect it is good news. However it is likely to be a long journey between this point and having an effective treatment available. Even when the disease-causing mechanism is adequately understood, the quest for potential effective treatments is by no means automatic or straightforward, and even when a promising candidate is defined, then starts the expensive and arduous clinical trials process to establish safety and effectiveness.

  2. Dolores posted at 12:46 am on 7 February 2018Reply

    My daughter is 30 yrs old and was diagnosed with SPG-11 a few yrs ago. She is using braces to help her
    walk. Thank you for your continuous work as we continue to hope for other treatments.
    Teresa, where do you live? We live in Virginia.

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