A beta-induced mitochondrial dysfunction in neural progenitors controls KDM5A to influence neuronal differentiation

Abstract

Mitochondria in neural progenitors play a crucial role in adult hippocampal neurogenesis by being involved in fate decisions for differentiation. However, the molecular mechanisms by which mitochondria are related to the genetic regulation of neuronal differentiation in neural progenitors are poorly understood. Here, we show that mitochondrial dysfunction induced by amyloid-beta (A beta) in neural progenitors inhibits neuronal differentiation but has no effect on the neural progenitor stage. In line with the phenotypes shown in Alzheimer's disease (AD) model mice, A beta-induced mitochondrial damage in neural progenitors results in deficits in adult hippocampal neurogenesis and cognitive function. Based on hippocampal proteome changes after mitochondrial damage in neural progenitors identified through proteomic analysis, we found that lysine demethylase 5A (KDM5A) in neural progenitors epigenetically suppresses differentiation in response to mitochondrial damage. Mitochondrial damage characteristically causes KDM5A degradation in neural progenitors. Since KDM5A also binds to and activates neuronal genes involved in the early stage of differentiation, functional inhibition of KDM5A consequently inhibits adult hippocampal neurogenesis. We suggest that mitochondria in neural progenitors serve as the checkpoint for neuronal differentiation via KDM5A. Our findings not only reveal a cell-type-specific role of mitochondria but also suggest a new role of KDM5A in neural progenitors as a mediator of retrograde signaling from mitochondria to the nucleus, reflecting the mitochondrial status. Alzheimer's disease: a molecular link with mitochondrial damage Neural Stem cells in the brain that normally generate new neurons throughout life can become dysfunctional due to damage caused by the protein amyloid-beta to mitochondria, the intracellular energy-producing structures. Neuron generation is reduced in Alzheimer's disease, therefore understanding its causes could lead to new treatments. Dong Kyu Kim at Seoul National University, South Korea, and colleagues studied neuron generation in the hippocampus region of mouse brains. They found that the protein amyloid-beta, implicated in causing Alzheimer's, can induce dysfunctional neuron generation by damaging mitochondria in a way that affects the activity of a gene-regulating protein called KDM5A. The research reveals a central role for mitochondria of neural stem cells in neuron generation, and suggests that drugs supporting mitochondrial function might offer a new approach to treat Alzheimer's and perhaps other degenerative brain diseases.