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Towards an hNPC-based Treatment for Neurodegenerative Diseases

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Review of “Human Neural Progenitor Transplantation Rescues Behavior and Reduces -Synuclein in a Transgenic Model of Dementia with Lewy Bodies” from Stem Cells Translational Medicine by Stuart P. Atkinson

The misfolding and accumulation of the presynaptic protein -synuclein (-syn) into insoluble aggregates represents a common feature of neurodegenerative diseases such as Alzheimer’s and Huntington’s disease, and also Dementia with Lewy Bodies (DLB). Recently, therapeutic strategies to combat these diseases have turned to neural stem/progenitor cell (NSC/NPC) transplantation and the group of Mathew Blurton-Jones (University of California, Irvine, USA) has previously demonstrated that the transplantation of mouse NSCs can recover both motor and cognitive deficits in a transgenic model of DLB [1]. 

In their new Stem Cells Translational Medicine article, the authors now propel this strategy closer to clinical application employing a well-characterized, genetically unmodified human neuronal progenitor cell (hNPC) line derived from the fetal cortex [2, 3] in a new immune-deficient transgenic model which more faithfully recapitulates DLB pathology. Will their new findings assist in the construction of an hNPC-based treatment for neurodegenerative diseases such as DLB in human patients [4]?

As a model for human DLB, the study created an -syn (ASO) transgenic mouse strain that develops human -syn inclusions in the expected brain areas but lacked a B-, T-, and Natural killer (NK) cell immune system. These mice also displayed DLB-associated motor and cognitive impairments; however, injections of hNPCs into the dorsal striatum, involved in both motor function and learning/memory, mediated the rescue of DLB symptoms.

Analysis of the injected cells demonstrated both hNPC survival and engraftment at the injection site but also extensive migration (See Figure), with migrating cells differentiating towards a predominantly astrocytic fate. Furthermore, hNPC transplantation also restored the striatal dopamine and glutamate neurotransmitter systems which are lost in ASO transgenic mice displaying motor and cognitive dysfunction [1].

But what about the -synuclein aggregates? Interestingly, the study found that hNPC transplantation exhibited no notable effect on -syn inclusions, but instead, hNPCs induced a reduction in soluble -syn monomers and oligomers, which the authors suggest is key to the observed improvements in neurotransmission and behavior. 

The study has propelled hNPC-based treatment strategies for neurodegenerative diseases further towards the clinic, although the authors do note that, as always, more work awaits. This will include studies of the different forms of oligomeric -syn species encountered, safety profiling over extended periods of time, optimization of hNPC survival and integration following transplantation, as well as testing hNPC treatment in other -syn-associated disorders, such as viral -synuclein models of Parkinson’s disease [5].

Stay tuned to the Stem Cells Portal to keep up to date with the future studies.

References

  1. Goldberg NR, Caesar J, Park A, et al. Neural Stem Cells Rescue Cognitive and Motor Dysfunction in a Transgenic Model of Dementia with Lewy Bodies through a BDNF-Dependent Mechanism. Stem Cell Reports 2015;5:791-804.
  2. McBride JL, Behrstock SP, Chen EY, et al. Human neural stem cell transplants improve motor function in a rat model of Huntington's disease. J Comp Neurol 2004;475:211-219.
  3. Shelley BC, Gowing G, and Svendsen CN. A cGMP-applicable expansion method for aggregates of human neural stem and progenitor cells derived from pluripotent stem cells or fetal brain tissue. J Vis Exp 2014.
  4. Goldberg NRS, Marsh SE, Ochaba J, et al. Human Neural Progenitor Transplantation Rescues Behavior and Reduces α-Synuclein in a Transgenic Model of Dementia with Lewy Bodies. STEM CELLS Translational Medicine 2017; In Press.
  5. Decressac M, Mattsson B, Lundblad M, et al. Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of alpha-synuclein in midbrain dopamine neurons. Neurobiol Dis 2012;45:939-953.