Highlights d The human FASN R1819W variant affects neurogenesis and cognition in knockin mice d FASN R1819W impairs human neural stem/progenitor cell (NSPC) proliferation d FASN-dependent metabolism differentially regulates NSPC activity in mice and humans

Cell–extracellular matrix (ECM) and cell–cell adhesion are interdependent during dorsal closure in the fly. Cell–ECM adhesion is required for normal myosin dynamics and organization of both cell–cell adhesions and actin networks during dorsal closure. Loss of cell–cell adhesion affects cell–ECM adhesion and tissue biomechanics.

Parkinson’s disease is the second most common neurodegenerative disease and yet the early pathophysiological events of the condition and sequences of dysfunction remain unclear. The loss of dopaminergic neurons and reduced levels of striatal dopamine are descriptions used interchangeably as underlying the motor deficits in Parkinson’s Disease. However, decades of research suggest that dopamine release deficits in Parkinson’s Disease do not occur only after cell death, but that there is dysfunction or dysregulation of axonal dopamine release before cell loss. Here we review the evidence for dopamine release deficits prior to neurodegeneration in Parkinson’s Disease, drawn from a large and emerging range of Parkinson’s Disease models, and the mechanisms by which these release deficits occur. The evidence indicates that impaired dopamine release can result from disruption to a diverse range of Parkinson’s Disease-associated genetic and molecular disturbances, and can be considered as a potential pathophysiological hallmark of Parkinson’s Disease.

Motor neuron diseases such as amyotrophic lateral sclerosis are primarily characterized by motor neuron degeneration with additional involvement of non-neuronal cells, in particular, microglia. In previous work, we have established protocols for the differentiation of iPSC-derived spinal motor neurons and microglia. Here, we combine both cell lineages and establish a novel co-culture of iPSC-derived spinal motor neurons and microglia, which is compatible with motor neuron identity and function. Co-cultured microglia express key identity markers and transcriptomically resemble primary human microglia, have highly dynamic ramifications, are phagocytically competent, release relevant cytokines and respond to stimulation. Further, they express key amyotrophic lateral sclerosis-associated genes and release disease-relevant biomarkers. This novel and authentic human model system facilitates the study of physiological motor neuron-microglia crosstalk and will allow the investigation of non-cell-autonomous phenotypes in motor neuron diseases such as amyotrophic lateral sclerosis.