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Parkinson variant impedes dopaminergic neurogenesis

Loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, a region critical for modulating motor movement and reward functions, leads to Parkinson disease (PD), a progressive neurodegenerative disease that currently has no cure. Recent work has shown that neurogenesis can occur in the adult brain and that genes associated with PD, including SNCA, PINK1, and LRRK2, may regulate neurogenesis. However, whether adult dopaminergic neurons or other disease-related neuronal populations are generated or turned over in adulthood remains an open question. In a recent study published in Scientific Reports (, Brown and colleagues show that PINK1 deficiency impairs dopaminergic neurogenesis in two model systems. The findings may impact therapeutic approaches for PD in humans with biallelic PINK1 deficiency. The researchers first assessed cells in the zebrafish rostral posterior tuberculum (PT), a proliferative zone that harbors distinct populations of dopaminergic (DA) neurons. They found that the number of DA neurons in the PT increased between gestation and young adulthood in three of the four neuronal populations they evaluated. They next used EdU pulse-chase analyses in 3-month-old zebrafish to find that de novo generation of two populations of parvocellular neurons occurred in the adult rostral PT. A follow-up experiment, however, revealed that neurogenesis decreased between 3 and 12 months of age, as well as between 3 and 22 months of age. Lineage tracing confirmed the results. The team then performed similar experiments in zebrafish lacking pink1. They found that although pink1−/− zebrafish generated new DA neurons in the rostral PT in numbers similar to those in wild-type fish up to 3 months of age, the number of new DA neurons did not expand significantly between 3 and 24 months as they did in wild-type fish. By 24 months of age, the number of DA neurons in pink1−/− zebrafish was significantly lower than in wild-type fish. Lastly, the researchers generated isogenic human midbrain-specific organoids from small molecule–derived neural progenitor cells. Organoids lacking PINK1 showed a reduced growth rate compared with isogenic controls. These organoids also showed a significantly reduced proportion of Tuj1/TH double positive DA neurons over time, indicating that the lack of PINK1 impaired DA neuronal differentiation. Taking these findings together, the authors conclude that they support the idea that factors impacting de novo neuronal generation may contribute to PD pathology, with potential implications for future therapeutic approaches. V. L. Dengler, News Editor

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Targeted therapy for tooth regeneration proves viable

Different species each have a specific number of teeth. Dogs have 42 permanent teeth, for example, whereas mice only have 16. Most adult humans have 32 permanent teeth. However, this number can vary in about 1% of individuals, leading to more teeth, known as supernumerary teeth, or fewer teeth, labeled tooth agenesis. Hypodontia is the developmental absence of one or more teeth. Arrested tooth development leads to tooth agenesis. Research in knockout mouse models has identified several responsible genes, including Msx1, Runx2, Ectodysplasin A (EDA), and Pax9. In contrast, loss of function of another gene, uterine sensitization-associated gene 1 (USAG1), results in supernumerary teeth. While researchers have demonstrated that USAG1 can rescue tooth agenesis in a genetic mouse model, whether local inhibition of USAG1 function can rescue tooth agenesis remains unknown. In a recent study published in Science Advances (, Murashima-Suginami and colleagues found that a single systemic administration of USAG1-neutralizing antibodies rescued tooth agenesis in EDA1-deficient mice. The findings indicate that molecular therapy targeting USAG1 may be an effective approach for tooth regenerative therapy. The researchers first showed that mice lacking both USAG1 and EDA1 had normal teeth, supernumerary teeth, or fused mandibular molars, whereas mice lacking EDA1 but expressing USAG1 had molar hypodontia, confirming that USAG1−/− can rescue congenital tooth agenesis. Next, the researchers generated five mouse USAG1 monoclonal antibodies and systemically administered each antibody to EDA1−/− pregnant mice. Four of the five antibodies rescued mandibular molar hypodontia. A different set of four USAG1 monoclonal antibodies resulted in supernumerary teeth. One of the antibodies also induced supernumerary teeth in wild-type animals. Two of the antibodies reversed hypodontia at a high rate and in a dose-dependent manner. In vitro analyses revealed that these two USAG1 antibodies neutralized the antagonizing effect of USAG1 on bone morphogenetic protein (BMP) signaling. The findings suggest that BMP signaling is essential for tooth development in mice. Finally, to confirm that USAG1 neutralizing antibodies affect BMP signaling to generate a whole new tooth in a nonrodent model, the researchers systemically administered one of the antibodies to postnatal ferrets, which have a dental pattern similar to that in humans. After three administrations and immunosuppression, the researchers observed supernumerary tooth formation. Taken together, the researchers conclude that USAG1 prevents the growth of tooth primordia and that systemic administration of USAG1-neutralizing antibodies rescues tooth agenesis and produces supernumerary teeth in animal models, providing support for further investigation into a promising therapeutic approach for tooth regeneration. —V. L. Dengler, News Editor

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News. Genet Med 23, 978 (2021).

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