Search

Microglia are crucial for maintaining brain health and neuron function. Here, we report that microglia establish connections with neurons using tunneling nanotubes (TNTs) in both physiological and pathological conditions. These TNTs facilitate the rapid exchange of organelles, vesicles, and proteins. In neurodegenerative diseases like Parkinson's and Alzheimer's disease, toxic aggregates of alpha-synuclein (α-syn) and tau accumulate within neurons. Our research demonstrates that microglia use TNTs to extract neurons from these aggregates, restoring neuronal health. Additionally, microglia share their healthy mitochondria with burdened neurons, reducing oxidative stress and normalizing gene expression. Disrupting mitochondrial function with antimycin A before TNT formation eliminates this neuroprotection. Moreover, co-culturing neurons with microglia and promoting TNT formation rescues suppressed neuronal activity caused by α-syn or tau aggregates. Notably, TNT-mediated aggregate transfer is compromised in microglia carrying Lrrk22(Gly2019Ser) or Trem2(T66M) and (R47H) mutations, suggesting a role in the pathology of these gene variants in neurodegenerative diseases., Competing Interests: Declaration of interests E.L. is a co-founder and advisor at IFM Therapeutics, and M.T.H. serves as an advisory board member at IFM Therapeutics, T3D, and Alector., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

There is a continued unmet need for treatments that can slow Parkinson's disease progression due to the lack of understanding behind the molecular mechanisms underlying neurodegeneration. Since its discovery, ferroptosis has been implicated in several diseases and represents a therapeutic target in Parkinson's disease. Here, we use two highly relevant human dopaminergic neuronal models to show that endogenous levels of α-synuclein can determine the sensitivity of dopaminergic neurons to ferroptosis. We show that reducing α-synuclein expression in dopaminergic neurons leads to ferroptosis evasion, while elevated α-synuclein expression in patients' small-molecule-derived neuronal precursor cells with SNCA triplication causes an increased vulnerability to lipid peroxidation and ferroptosis. Lipid profiling reveals that ferroptosis resistance is due to a reduction in ether-linked phospholipids, required for ferroptosis, in neurons depleted of α-synuclein (α-syn). These results provide a molecular mechanism linking α-syn levels to the sensitivity of dopaminergic neurons to ferroptosis, suggesting potential therapeutic relevance., Competing Interests: Declaration of interests D.D. has received PHRC grants from the French Ministry of Health and research funding from the ARSLA charity, France Parkinson charity, and the Credit Agricole Foundation. He has led two pilot investigator-driven studies with DFP provided for free by ApoPharma (FAIRPARK-I and SAFE-FAIR ALS-I). He is leading two large investigator-driven studies with DFP provided for free by ApoPharma (FAIRPARK-II and FAIR ALS-II). He served on advisory boards, served as a consultant, and has given lectures for pharmaceutical companies such as Orkyn, Aguettant, Abbvie, Medtronic, Novartis, Teva, UCB, and Lundbeck. J.A.D. has received research funding from Alzheimer’s Society, Alzheimer’s Research UK, European Commission, Parkinson’s UK, and NHMRC. He serves as a scientific advisor on the FAIR-PARK II but has no financial disclosures. The remaining authors have nothing to declare., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Research on human brain development and neurological diseases is limited by the lack of advanced experimental in vitro models that truly recapitulate the complexity of the human brain. Here, we describe a robust human brain organoid system that is highly specific to the midbrain derived from regionally patterned neuroepithelial stem cells. These human midbrain organoids contain spatially organized groups of dopaminergic neurons, which make them an attractive model for the study of Parkinson's disease. Midbrain organoids are characterized in detail for neuronal, astroglial, and oligodendrocyte differentiation. Furthermore, we show the presence of synaptic connections and electrophysiological activity. The complexity of this model is further highlighted by the myelination of neurites. The present midbrain organoid system has the potential to be used for advanced in vitro disease modeling and therapy development., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)