scholarly journals The proportion of mutations predicted to have a deleterious effect differs between gain and loss of function genes in neurodegenerative disease

2009 ◽  
Vol 30 (3) ◽  
pp. E481-E489 ◽  
Author(s):  
Paul N. Valdmanis ◽  
Dominique J. Verlaan ◽  
Guy A. Rouleau
Keyword(s):  
Neurodegenerative Disease ◽  
Deleterious Effect ◽  
Loss Of Function ◽  
Gain And Loss

scholarly journals Gain- and loss-of-function mutations inZat10enhance the tolerance of plants to abiotic stress

FEBS Letters ◽  
2006 ◽  
Vol 580 (28-29) ◽  
pp. 6537-6542 ◽  
Author(s):  
Ron Mittler ◽  
YongSig Kim ◽  
Luhua Song ◽  
Jesse Coutu ◽  
Alicia Coutu ◽  
...  
Keyword(s):  
Abiotic Stress ◽  
Loss Of Function ◽  
Gain And Loss

Abstract 1100: Gain and loss of function genome-wide CRISPR screens identify Hippo signaling as an important driver of resistance inEGFRmutant lung cancer

2021 ◽  
Author(s):  
Matthias Pfeifer ◽  
Jonathan S. Brammeld ◽  
Stacey Price ◽  
Matthew Martin ◽  
Hannah Thorpe ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Hippo Signaling ◽  
Loss Of Function ◽  
Genome Wide ◽  
Gain And Loss

scholarly journals Loss of TBK1 activity leads to TDP-43 proteinopathy through lysosomal dysfunction in human motor neurons

2021 ◽  
Author(s):  
Jin Hao ◽  
Michael F Wells ◽  
Gengle Niu ◽  
Irune Guerra San Juan ◽  
Francesco Limone ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Neurodegenerative Disease ◽  
Motor Neurons ◽  
Inhibition Mechanism ◽  
Loss Of Function ◽  
Neurodegenerative Process ◽  
Lysosomal Dysfunction ◽  
Human Motor ◽  
Lateral Sclerosis ◽  
Lysosomal Acidification

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss accompanied by cytoplasmic localization of TDP-43 proteins and their insoluble accumulations. Haploinsufficiency of TBK1 has been found to associate with or cause ALS. However, the cell-autonomous mechanisms by which reduced TBK1 activity contributes to human motor neuron pathology remain elusive. Here, we generated a human cellular model harboring loss-of-function mutations of TBK1 by gene editing and found that TBK1 deficiency was sufficient to cause TDP-43 pathology in human motor neurons. In addition to its functions in autophagy, we found that TBK1 interacted with endosomes and was required for normal endosomal maturation and subsequent lysosomal acidification. Surprisingly, TDP-43 pathology resulted more from the dysfunctional endo-lysosomal pathway than the previously recognized autophagy inhibition mechanism. Restoring TBK1 levels ameliorated lysosomal dysfunction and TDP-43 pathology and maintained normal motor neuron homeostasis. Notably, using patient-derived motor neurons, we found that haploinsufficiency of TBK1 sensitized neurons to lysosomal stress, and chemical regulators of endosomal maturation rescued the neurodegenerative process. Together, our results revealed the mechanism of TBK1 in maintaining TDP-43 and motor neuron homeostasis and suggested that modulating endosomal maturation was able to rescue neurodegenerative disease phenotypes caused by TBK1 deficiency.

scholarly journals Small Molecule Stabilization of PINK-1/PINK1 Improves Neurodegenerative Disease

2021 ◽  
Author(s):  
Elissa Tjahjono ◽  
Jingqi Pei ◽  
Alexey V Revtovich ◽  
Terri-Jeanne E Liu ◽  
Alisha Swadi ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Mitochondrial Fragmentation ◽  
Atp Production ◽  
C Elegans ◽  
Mitochondrial Homeostasis ◽  
Phenotypic Screen ◽  
Gfp Reporter ◽  
Common Causes

Macroautophagic recycling of dysfunctional mitochondria, known as mitophagy, is essential for mitochondrial homeostasis and cell viability. Accumulation of defective mitochondria and impaired mitophagy have been widely implicated in many neurodegenerative diseases, and loss-of-function mutations of two regulators of mitophagy, PINK1 and Parkin, are amongst the most common causes of recessive Parkinson's disease. Activation of mitophagy via pharmacological treatments may be a feasible approach for combating neurodegeneration. In this effort, we screened ~45,000 small molecules for the ability to activate mitophagy. A high-throughput, whole-organism, phenotypic screen was conducted by monitoring stabilization of PINK-1/PINK1, a key event in mitophagy activation, in a Caenorhabditis elegans strain carrying a Ppink-1::PINK-1::GFP reporter. We obtained eight hits that induced mitophagy, as evidenced by increased mitochondrial fragmentation and autophagosome formation. Several of the compounds also reduced ATP production, oxygen consumption, mitochondrial mass, and/or mitochondrial membrane potential. Importantly, we found that treatment with two compounds, which we named PS83 and PS106 (more commonly known as sertraline) reduced neurodegenerative disease phenotypes (including delayed paralysis in a C. elegans Alzheimer's model) in a PINK-1/PINK1-dependent manner. This report presents a promising step toward the identification of compounds that will stimulate mitochondrial turnover.

scholarly journals Mitofusin gain and loss of function drive pathogenesis in Drosophila models of CMT 2A neuropathy

EMBO Reports ◽  
2018 ◽  
Vol 19 (8) ◽  
Author(s):  
Najla El Fissi ◽  
Manuel Rojo ◽  
Aїcha Aouane ◽  
Esra Karatas ◽  
Gabriela Poliacikova ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Gain And Loss ◽  
Drosophila Models

scholarly journals Gain and Loss of Function of P2X7 Receptors: Mechanisms, Pharmacology and Relevance to Diabetic Neuropathic Pain

2014 ◽  
Vol 10 ◽  
pp. 1744-8069-10-37 ◽  
Author(s):  
Daniel Ursu ◽  
Philip Ebert ◽  
Emily Langron ◽  
Cara Ruble ◽  
Leanne Munsie ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Loss Of Function ◽  
Diabetic Neuropathic Pain ◽  
P2x7 Receptors ◽  
Gain And Loss
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