Multiplication of the SNCA locus exacerbates neuronal nuclear aging
Lidia Tagliafierro1,2, Madison Elena Zamora1,2, Ornit Chiba-Falek1,2
1Department of Neurology, Duke University Medical Center, Durham, NC, USA.
Human Molecular Genetics
|October 11, 2018
Summary
Researchers developed aged human induced pluripotent stem cell (hiPSC)-derived neurons to model Parkinson's disease. Aged neurons from a Parkinson's patient showed accelerated nuclear aging and increased alpha-synuclein aggregates.
Area of Science:
- Neuroscience
- Stem Cell Biology
- Genetics
Background:
- Human induced pluripotent stem cell (hiPSC)-derived neurons are valuable models for neurodegenerative diseases like Parkinson's disease (PD).
- Existing hiPSC models represent rejuvenated neurons, not reflecting the age-related risk factor in PD.
- Aging is a significant risk factor for neurodegenerative disorders, necessitating models that incorporate this aspect.
Purpose of the Study:
- To develop and validate a method for generating aged dopaminergic and cholinergic neurons from hiPSCs.
- To model Parkinson's disease and related synucleinopathies using these aged neuronal models.
- To investigate the interplay between aging and genetic factors (SNCA overexpression) in neuronal pathology.
Main Methods:
- Developed a novel 'semi-natural' aging process for hiPSC-derived neurons by extended passaging at the Neural Precursor Cell stage.
- Validated the aging induction method using markers of heterochromatin, nuclear envelope, DNA damage, and global DNA methylation.
- Compared isogenic hiPSC-derived neurons from a patient with SNCA-triplication (SNCA-Tri) and a control, at both juvenile and aged stages.
Main Results:
- The age-inducing method successfully generated aged hiPSC-derived neurons with validated aging signatures.
- SNCA-Tri neurons exhibited exacerbated nuclear aging, with advanced aging markers even at the juvenile stage.
- Aged SNCA-Tri neurons displayed significantly more alpha-synuclein aggregates compared to juvenile SNCA-Tri neurons.
Conclusions:
- The developed method effectively models neuronal aging relevant to Parkinson's disease.
- SNCA overexpression exacerbates nuclear aging in hiPSC-derived neurons.
- A potential link exists between neuronal aging and SNCA overexpression in the context of nuclear architecture and alpha-synuclein aggregation.
Related Concept Videos
01:49Multiple Allele Traits
38.1K
The Concept of Multiple Allelism
38.1K
02:45Nuclear Fusion
33.9K
The process of converting very light nuclei into heavier nuclei is also accompanied by the conversion of mass into large amounts of energy, a process called fusion. The principal source of energy in the sun is a net fusion reaction in which four hydrogen nuclei fuse and ultimately produce one helium nucleus and two positrons.
A helium nucleus has a mass that is 0.7% less than that of four hydrogen nuclei; this lost mass is converted into energy during the fusion. This reaction produces about...
A helium nucleus has a mass that is 0.7% less than that of four hydrogen nuclei; this lost mass is converted into energy during the fusion. This reaction produces about...
33.9K
01:26Locus of Control
219
Locus of control describes how individuals perceive the causes of events in their lives, influencing motivation and well-being. Introduced by Julian Rotter in 1954, it is categorized into internal and external locus of control.Internal Locus of ControlIndividuals with an internal locus of control believe their actions determine outcomes, fostering responsibility, self-efficacy, and motivation. For example, an employee may attribute career success to hard work. Research links this mindset to...
219
02:36Nuclear Power
9.5K
Controlled nuclear fission reactions are used to generate electricity. Any nuclear reactor that produces power via the fission of uranium or plutonium by bombardment with neutrons has six components: nuclear fuel consisting of fissionable material, a nuclear moderator, a neutron source, control rods, reactor coolant, and a shield and containment system.
Nuclear Fuels
Nuclear fuel consists of a fissile isotope, such as uranium-235, which must be present in sufficient quantity to provide a...
Nuclear Fuels
Nuclear fuel consists of a fissile isotope, such as uranium-235, which must be present in sufficient quantity to provide a...
9.5K
03:18Nuclear Stability
23.3K
Protons and neutrons, collectively called nucleons, are packed together tightly in a nucleus. With a radius of about 10−15 meters, a nucleus is quite small compared to the radius of the entire atom, which is about 10−10 meters. Nuclei are extremely dense compared to bulk matter, averaging 1.8 × 1014 grams per cubic centimeter. If the earth’s density were equal to the average nuclear density, the earth’s radius would be only about 200 meters.
To hold positively charged protons together...
To hold positively charged protons together...
23.3K
01:29Non-nuclear Inheritance
23.2K
Most DNA resides in the nucleus of a cell. However, some organelles in the cell cytoplasm—such as chloroplasts and mitochondria—also have their own DNA. These organelles replicate their DNA independently of the nuclear DNA of the cell in which they reside. Non-nuclear inheritance describes the inheritance of genes from structures other than the nucleus.
23.2K