Understanding the autophagy-linked disorder BPAN: an integrated approach for studying developmental basis of neurodegenerative diseases

Información del proyecto

NeuroDiDro

Identificador del acuerdo de subvención: 101067877

DOI

10.3030/101067877

Proyecto cerrado

Fecha de la firma de la CE 28 Junio 2022

Fecha de inicio 1 Octubre 2022

Fecha de finalización 30 Septiembre 2024

Financiado con arreglo a

• Marie Skłodowska-Curie Actions (MSCA)

Coste total

Sin datos

Aportación de la UE

€ 209 884,88

Coordinado por

ECOLE NORMALE SUPERIEURE DE LYON
France

Periodic Reporting for period 1 - NeuroDiDro (Understanding the autophagy-linked disorder BPAN: an integrated approach for studying developmental basis of neurodegenerative diseases)

Período documentado: 2022-10-01 hasta 2024-09-30

Resumen del contexto y de los objetivos generales del proyecto

Understanding the fundamental basis of brain disorders is one of the most pressing challenges of the 21st century, as highlighted by the Lancet Global Burden of Disease Resource Centre. Brain disorders include conditions that manifest both neurodevelopmental defects and later-onset neurodegeneration. Large-scale genetic studies have identified numerous genes associated with both neurodevelopmental and neurodegenerative disorders, indicating that these conditions may share common mechanisms. Despite this progress, it is currently unclear to what extent the adult-onset neurodegenerative disorder is linked to early developmental defects, and whether these two stages of disease rely on common or different neural and genetic operators.
Autophagy is a cellular mechanism, which dysfunction during development or in adult can lead to neurodegenerative, including beta-propeller protein-associated neurodegeneration (BPAN). BPAN is an emerging disorder caused by mutations in the autophagy-related gene Wdr45. It is characterized by both neurodevelopmental and adult-specific phases, providing a unique opportunity to explore the links between these phases and better understand disease progression.
Over the decades, the fruit fly Drosophila melanogaster has been widely utilized as a model organism to study various neurological disorders and gain insights into neurodegeneration. In this project, we use Drosophila to investigate the connection between neurodevelopment and neurodegenerative disorders. Specifically within the model of Beta Propeller Associated Neurodegeneration (BPAN) induced by WDR45, our research focuses on this gene paralog, CG11975 (referred to here as DmWdr45), to elucidate the mechanisms linking neurodevelopmental defects and neurodegenerative phenotypes.
The experimental design included systematic, longitudinal in vivo screenings to record behavioral changes from embryonic stages through adulthood, alongside cellular and molecular analyses. By conducting experiments at various developmental stages in the WDR45-linked disorder, this study aims to provide a comprehensive understanding of the co-occurrence of neurodevelopmental defects and neurodegenerative processes in BPAN.
The overarching goal of this project was to elucidate the mechanisms linking neurodevelopmental defects and neurodegenerative phenotypes in the fly model of BPAN related to DmWdr45 loss-of-function. The project was structured into three interleaving aims, ordered from short- to long-term goals: (i) identifying the effects of Wdr45 mutation on Drosophila early brain function; (ii) determining the neural basis of neurodevelopmental defects and neurodegenerative phenotypes in Wdr45-linked disorders and (iii) linking neurodevelopmental defects to neurodegenerative phenotypes.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

-Constructed a behavioral setup and systematically screened for motor behavior changes in DmWdr45 mutants from embryonic to larval stages.
-Used immunolabeling techniques to investigate cellular alterations in the DmWdr45 mutant brains by quantifying oxidative stress accumulations.
-Through bioinformatics, genetic tools, and behavioral analysis, we established that DmWdr45 is primarily required in neurons rather than glial cells. We observed that neuronal projections in DmWdr45 mutants are altered early in development at the embryonic stages.
-We are currently mapping neural circuits that contribute to early developmental defects and adult-onset phenotypes in Wdr45 Drosophila mutants.
-Completed proteomic analyses to identify molecular alterations in DmWdr45 mutants. Work is ongoing to disentangle neurodevelopmental defects from adult-onset phenotypes in DmWdr45 mutants

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

Our results showed that a loss-of-function mutation in DmWdr45 results in widespread neuronal dysfunction throughout the developmental stages of Drosophila, affecting motor programs in embryos, larvae, and adults. These fundings also suggest that adult locomotor defects originate from the embryonic. Our analysis of single-cell RNA sequencing data, immunolabeling techniques, and RNAi tools demonstrated that DmWdr45 expression is predominantly required in neurons, not in glia cells, for normal brain function. At the cellular level, our observations indicated that the loss-of-function mutation in DmWdr45 disrupts normal axonal development at early stages, resulting in aberrant axonal projections and commissure formation in embryos. These disruptions likely contribute to the observed impairment in motor control, as proper axonal targeting and connectivity are essential for the execution of coordinated motor programs. Overall, our results provide insight into the autophagy-linked disorder BPAN, which includes both developmental and adulthood defects in the nervous system. This contributes to a better understanding of the co-occurrence of developmental and neurodegenerative defects during diseases such as Parkinson's and Huntington's.