Wieland B Huttner ^*

• Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society, Dresden, Germany

One strategy in the treatment of neurodegenera=ve diseases has been towards replenishing the lost cells, notably neurons. Approaches taken to this end have included the following. First, to either ac=vate neural stem cells that endogenously exist in certain neurogenic niches of the adult human brain, such that new neurons are being generated where needed (for recent reviews, see (Temple, 2023, Vassal et al., 2024, Velikic et al., 2024)). Second, to graS exogenous neural stem cells and/or exogenously generated neurons into the affected brain region, oSen by making use of pa=ent-derived induced pluripotent stem cells (iPSCs) to obtain the former cells (for recent reviews, see (Lee et al., 2024, Temple, 2023, Vadodaria et al., 2020)).In this brief Opinion Ar=cle, I would like to draw aXen=on to the human-specific gene ARHGAP11B, which exhibits proper=es that could poten=ally be beneficial in the treatment of neurodegenera=ve diseases. ARHGAP11B is typically referred to as a human-specific gene. This statement is correct with regard to extant species, as ARHGAP11B does not occur in any other primate nor other mammal. However, from an evolu=onary point of view, ARHGAP11B is actually a homininspecific gene, as it has been shown to have occurred in Neandertals and Denisovans, and in light of its origin ≈5 mya likely occurred in other members of the Homo lineage (for a recent review, see (HuXner et al., 2024)).A key feature with regard to ARHGAP11B being poten=ally an addi=onal tool in the treatment of neurodegenera=ve diseases pertains to the cell types where this gene is expressed. Thus, in fetal human neocortex, the cells exhibi=ng the highest level of ARHGAP11B expression are the neural stem and progenitor cells. Specifically, ARHGAP11B is expressed in both the apical progenitors residing in the ventricular zone and the basal progenitors residing in the subventricular zone, notably apical radial glia and basal (or outer) radial glia, respec=vely (Florio et al., 2015). Such expression can be seen as a strategic advantage if one intends to use cor=cal stem and progenitor cells for therapeu=c approaches in neurodegenera=ve diseases that aim to achieve cell replacement. Indeed, and of poten=al clinical relevance, expression of ARHGAP11B in various animal model systems in vivo has been shown to amplify basal progenitors, the progenitor cells that generate cor=cal neurons (Florio et al., 2015, Kalebic et al., 2018, Heide et al., 2020, Xing et al., 2021). Moreover, ARHGAP11B's effects on basal progenitors result in an increase in cor=cal neuron produc=on in vivo (Florio et al., 2015, Kalebic et al., 2018, Heide et al., 2020, Xing et al., 2021). Of note, ARHGAP11B expression in vivo increases the so-called upper-layer neurons, the class of cor=cal neurons implicated in higher cogni=ve abili=es (Kalebic et al., 2018, Heide et al., 2020, Xing et al., 2021). The amplifica=on of basal progenitors in vivo by ARHGAP11B is based on the ability of this gene to induce basal progenitor self-renewal (Florio et al., 2015, Kalebic et al., 2018, Heide et al., 2020). Hence, ARHGAP11B fulfills a key criterion for its poten=al therapeu=c applica=on in neuron replenishment strategies in the treatment of neurodegenera=ve diseases -the ability to induce, in vivo, the self-renewal of those progenitor cells that generate cor=cal neurons. To explore the poten=al use of ARHGAP11B as an addi=onal tool in the treatment of neurodegenera=ve diseases, approaches to be considered include the following two. First, one could aim at targe=ng the endogenous neural stem cells in the adult human brain with an appropriate ARHGAP11B expression vector. Neural stem cells and/or neurogenesis in the adult human brain have so far been detected in the hippocampus (for a review, see (KempermannSong and Gage, 2015)), the amygdala (Roeder et al., 2022), and the subventricular zone of the lateral ventricles (for a recent summary, see (Baig et al., 2024). An appropriate ARHGAP11B expression vector should feature an inducible on-off expression system to first amplify the respec=ve neural stem cells by switching on ARHGAP11B expression and thereaSer, upon switching off ARHGAP11B expression, to allow them to generate neurons.A second line of approach could make use of pa=ent-derived iPSCs that are first converted to neural stem cells, into which an appropriate ARHGAP11B expression system is then introduced. Such neural stem cells with the capacity to allow an inducible expression of ARHGAP11B could then be administered into the brain region of interest, followed by local neural stem cell amplifica=on and then local neurogenesis as above. Should the transient (i.e., inducible) expression of ARHGAP11B indeed lead to local neural stem cell amplifica=on and, consequently, local neuron replenishment, a key future task of this approach will be to determine whether the newly generated neurons are able to func=onally compensate for the lost neurons. If so, it could be forward-looking to consider the mechanism underlying the ability of ARHGAP11B to amplify neural stem cells. The ARHGAP11B protein has been shown to be imported into the matrix of mitochondria in the cells expressing this gene, where ARHGAP11B s=mulates the metabolic pathway called glutaminolysis (Namba et al., 2020). In light of the emerging concept that changes in metabolism exert crucial impact on the behaviour of neural stem cells (Namba et al., 2021), targe=ng specific metabolic pathways may aid future therapeu=c endeavours in the treatment of neurodegenera=ve diseases.