Mutations in a P-type ATPase gene cause axonal degeneration
Xianjun Zhu1, Richard T Libby, Wilhelmine N de Vries
1The Jackson Laboratory, Bar Harbor, Maine, United States of America.
Plos Genetics
|August 23, 2012
Summary
Mutations in the Atp8a2 gene cause axon degeneration and neurodegenerative disease in mice. This study identifies ATP8A2 as a key player in maintaining neuronal health and preventing neurodegeneration.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Axonal degeneration is a hallmark of neurodegenerative diseases, but its molecular causes are often unknown.
- The wabbler-lethal (wl) mouse model exhibits progressive ataxia and neurodegeneration, with its primary pathology debated as myelinopathy or axonopathy.
Purpose of the Study:
- To elucidate the molecular mechanisms of axonal degeneration in the wabbler-lethal (wl) mouse model.
- To determine the primary cause of neurodegeneration in wl mice and identify the causative gene.
Main Methods:
- Genetic analysis of wabbler-lethal (wl) mouse mutants.
- Assessment of axonal degeneration and neurodegeneration in wl mice.
- Biochemical analysis of ATP8A2 protein function, including phosphatidylserine translocase activity.
Main Results:
- Wabbler-lethal mutants exhibit a primary axonopathy, modulated by Wld(s) and Bax mutations.
- The gene responsible for the disease-causing mutations in wl mice was identified as Atp8a2.
- Mutations in Atp8a2 disrupt phosphatidylserine translocase activity, leading to axonal degeneration.
Conclusions:
- The study provides clear evidence that wabbler-lethal mutants suffer from axonopathy.
- Mutation of the Atp8a2 gene, encoding a phosphatidylserine translocase, causes axon degeneration and neurodegenerative disease in mammals.
- ATP8A2 dysfunction is implicated in the pathogenesis of neurodegenerative conditions.
Related Concept Videos
01:39Mutations
Overview
01:27ATP Driven Pumps I: An Overview
ATP-driven pumps, also known as transport ATPases, are integral membrane proteins. They have binding sites for ATP located on the membrane's cytosolic side and the ion-conducting domain in the transmembrane region. These pumps use the free energy released from ATP hydrolysis to move the solutes across cell membranes against an electrochemical gradient.
There are four main types of ATP-driven pumps - P-type, V-type, F-type, and ABC transporter. All these pumps are of varying complexities and are...
There are four main types of ATP-driven pumps - P-type, V-type, F-type, and ABC transporter. All these pumps are of varying complexities and are...
01:48ATP Synthase: Mechanism
In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased ATP...
01:18ATP Synthase: Structure
ATP synthase or ATPase is among the most conserved proteins found in bacteria, mammals, and plants. This enzyme can catalyze a forward reaction in response to the electrochemical gradient, producing ATP from ADP and inorganic phosphate. ATP synthase can also work in a reverse direction by hydrolyzing ATP and generating an electrochemical gradient. Different forms of ATP synthases have evolved special features to meet the specific demands of the cell. Based on their specific feature, ATP...
01:34ATP Driven Pumps II: P-type Pumps
The P-type pumps are a large family of integral membrane transporter ATPases. They are divided into five major types based on substrate specificity, from I to V.
A typical P-type pump has three cytosolic domains: nucleotide-binding (N), phosphorylation (P), and activator (A) domains. These domains are connected to the membrane-spanning helices by short amino acid segments. ATP hydrolysis and covalent phosphoenzyme intermediate formation are crucial parts of the catalytic cycle. At the highly...
A typical P-type pump has three cytosolic domains: nucleotide-binding (N), phosphorylation (P), and activator (A) domains. These domains are connected to the membrane-spanning helices by short amino acid segments. ATP hydrolysis and covalent phosphoenzyme intermediate formation are crucial parts of the catalytic cycle. At the highly...
01:30ATP Driven Pumps III: V-type Pumps
V-type pumps are ATP-driven pumps found in the vacuolar membranes of plants, yeast, endosomal and lysosomal membranes of animal cells, plasma membranes of a few specialized eukaryotic cells, and some prokaryotes. They are also known as the V1Vo-ATPase, that couple ATP hydrolysis to transport protons against a concentration gradient.
The peripheral or cytosolic V1 domain with eight subunits is involved in ATP hydrolysis. The integral or transmembrane V0 domain containing at least five subunits...
The peripheral or cytosolic V1 domain with eight subunits is involved in ATP hydrolysis. The integral or transmembrane V0 domain containing at least five subunits...