Functional Impairment in Miro Degradation and Mitophagy Is a Shared Feature in Familial and Sporadic Parkinson's Disease.

Mitochondrial movements are tightly controlled to maintain energy homeostasis and prevent oxidative stress. Miro is an outer mitochondrial membrane protein that anchors mitochondria to microtubule motors and is removed to stop mitochondrial motility as an early step in the clearance of dysfunctional mitochondria. Here, using human induced pluripotent stem cell (iPSC)-derived neurons and other complementary models, we build on a previous connection of Parkinson's disease (PD)-linked PINK1 and Parkin to Miro by showing that a third PD-related protein, LRRK2, promotes Miro removal by forming a complex with Miro.

Stage-specific role for shh in dopaminergic differentiation of human embryonic stem cells induced by stromal cells.

Stromal cells have been used to induce dopaminergic differentiation of mouse, primate, and human embryonic stem cells (hESCs), but the mechanism that governs this induction is unknown. In this manuscript, we show that medium conditioned by the stromal cell line PA6 (PA6-CM) can induce dopaminergic differentiation in neural stem cells (NSCs) derived from hESCs but not directly from hESCs, indicating that soluble factors produced by PA6 cells act at the NSC stage to specify a dopaminergic fate. To identify such soluble factors, we analyzed the transcriptomes of PA6 cells, NSCs, and dopaminergic populations induced by PA6-CM from hESC-derived NSCs.

Swiss Cheese, a protein involved in progressive neurodegeneration, acts as a noncanonical regulatory subunit for PKA-C3.

The Drosophila Swiss Cheese (SWS) protein and its vertebrate ortholog Neuropathy Target Esterase (NTE) are required for neuronal survival and glial integrity. In humans, NTE is the target of organophosphorous compounds which cause a paralyzing axonal degeneration and recently mutations in NTE have been shown to cause a Hereditary Spastic Paraplegia called NTE-related Motor-Neuron Disorder. SWS and NTE are concentrated in the endoplasmic reticulum and both have been shown to have an esterase function against an artificial substrate.

Human embryonic stem cells have enhanced repair of multiple forms of DNA damage.

Embryonic stem cells need to maintain genomic integrity so that they can retain the ability to differentiate into multiple cell types without propagating DNA errors. Previous studies have suggested that mechanisms of genome surveillance, including DNA repair, are superior in mouse embryonic stem cells compared with various differentiated murine cells. Using single-cell gel electrophoresis (comet assay) we found that human embryonic stem cells (BG01, I6) have more efficient repair of different types of DNA damage (generated from H2O2, UV-C, ionizing radiation, or psoralen) than human primary fibroblasts (WI-38, hs27) and, with the exception of UV-C damage, HeLa cells.

Loss of Swiss cheese/neuropathy target esterase activity causes disruption of phosphatidylcholine homeostasis and neuronal and glial death in adult Drosophila.

The Drosophila Swiss cheese (sws) mutant is characterized by progressive degeneration of the adult nervous system, glial hyperwrapping, and neuronal apoptosis. The Swiss cheese protein (SWS) shares 39% sequence identity with human neuropathy target esterase (NTE), and a brain-specific deletion of SWS/NTE in mice causes a similar pattern of progressive neuronal degeneration. NTE reacts with organophosphate compounds that cause a paralyzing axonal degeneration in humans and has been shown to degrade endoplasmic reticulum-associated phosphatidylcholine (PtdCho) in cultured mammalian cells.

Disruption of the MAP1B-related protein FUTSCH leads to changes in the neuronal cytoskeleton, axonal transport defects, and progressive neurodegeneration in Drosophila.

The elaboration of neuronal axons and dendrites is dependent on a functional cytoskeleton. Cytoskeletal components have been shown to play a major role in the maintenance of the nervous system through adulthood, and changes in neurofilaments and microtubule-associated proteins (MAPs) have been linked to a variety of neurodegenerative diseases. Here we show that Futsch, the fly homolog of MAP1B, is involved in progressive neurodegeneration.

Glial and neuronal expression of polyglutamine proteins induce behavioral changes and aggregate formation in Drosophila.

Patients with polyglutamine expansion diseases, like Huntington's disease or several spinocerebellar ataxias, first present with neurological symptoms that can occur in the absence of neurodegeneration. Behavioral symptoms thus appear to be caused by neuronal dysfunction, rather than cell death. Pathogenesis in polyglutamine expansion diseases is largely viewed as a cell-autonomous process in neurons.