Related Experiment Video
Updated: May 13, 2026
08:53
Assay to Measure Nucleocytoplasmic Transport in Real Time within Motor Neuron-like NSC-34 Cells
Published on: May 16, 2017
Pathophysiological insights into ALS with C9ORF72 expansions
Kelly L Williams1, Jennifer A Fifita, Steve Vucic
1Australian School of Advanced Medicine, Macquarie University, Sydney, New South Wales, Australia.
Journal of Neurology, Neurosurgery, and Psychiatry
|March 7, 2013
Summary
Expansions in C9ORF72 are a key genetic cause of amyotrophic lateral sclerosis (ALS). This study found cortical hyperexcitability in familial ALS linked to C9ORF72 expansions, with earlier onset in males.
Area of Science:
- Neuroscience
- Genetics
- Neurology
Background:
- Expansions of the C9ORF72 hexanucleotide repeat are a significant genetic cause of amyotrophic lateral sclerosis (ALS), affecting both familial and sporadic cases.
- Understanding the clinical and neurophysiological characteristics of ALS associated with C9ORF72 expansions is crucial for diagnosis and treatment.
Purpose of the Study:
- To investigate the clinical and neurophysiological features of familial and sporadic ALS patients with C9ORF72 expansions.
- To characterize the penetrance and age of onset in relation to C9ORF72 expansions.
- To explore potential oligogenic models in ALS pathogenesis.
Main Methods:
- Screening for C9ORF72 expansions in familial and sporadic ALS cohorts.
- Detailed clinical phenotyping of expansion-positive individuals.
- Utilizing threshold tracking transcranial magnetic stimulation (TMS) to assess cortical excitability, measuring motor evoked potentials (MEPs) in the abductor pollicis brevis.
Main Results:
- C9ORF72 expansions were identified in 38.5% of familial ALS and 3.5% of sporadic ALS cases.
- ALS penetrance showed gender-specific differences, with earlier onset in males.
- Cortical hyperexcitability was evident in C9ORF72-linked familial ALS, indicated by altered short-interval intracortical inhibition, cortical silent period, intracortical facilitation, and MEP amplitude.
Conclusions:
- C9ORF72 expansions are a major genetic factor in ALS, particularly familial forms.
- Cortical hyperexcitability is an intrinsic feature of C9ORF72-related familial ALS.
- The findings suggest potential gender-specific disease mechanisms and contribute to understanding ALS genetics and pathophysiology.
Related Concept Videos
01:24Parkinson Disease ll: Pathophysiology
Parkinson disease (PD) is a progressive neurodegenerative disorder primarily affecting movement, with additional non-motor features. Its pathophysiology involves complex interactions among genetic susceptibility, environmental exposures, and cellular dysfunction, including dopaminergic neuron loss, protein aggregation, and mitochondrial impairment.Selective NeurodegenerationA key feature is the degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to reduced...
01:23Alzheimer Disease ll: Pathophysiology
Alzheimer disease involves structural changes in the brain that begin long before symptoms appear. The most distinctive features are extracellular neuritic plaques and intracellular neurofibrillary tangles.Neuritic plaques form in the cerebral cortex and around blood vessels. These plaques contain a dense core of beta-amyloid (Aβ)—a toxic protein fragment that clumps outside neurons. The core is surrounded by damaged neuronal extensions, as well as reactive astrocytes and microglia. Abnormal...
03:03Amyloid Fibrils
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
01:29Alzheimer Disease l: Introduction
Alzheimer disease is a chronic, progressive, and irreversible neurodegenerative disorder and the most common cause of dementia in older adults. It leads to gradual neuronal loss, causing cognitive decline, behavioral changes, and loss of functional independence.Risk Factors and EtiologyThe disease is multifactorial. Age is the strongest risk factor, with prevalence doubling every 5 years after age 65. Genetic factors include mutations in genes such as APP, PSEN1, and PSEN2, which are associated...
01:22Lysosomal Hydrolases
Lysosomes are the site for the degradation of macromolecules and biological polymers released during membrane trafficking events such as secretory, endocytic, autophagic, and phagocytic pathways. The membrane-enclosed area of the lysosome, called the lumen, contains hydrolytic enzymes active in an acidic environment. These acid hydrolases are functional at a pH between 4.5 and 5 and are involved in cellular processes such as cell signaling, energy metabolism, restoration of the plasma membrane,...
01:37Neural Regulation
Digestion begins with a cephalic phase that prepares the digestive system to receive food. When our brain processes visual or olfactory information about food, it triggers impulses in the cranial nerves innervating the salivary glands and stomach to prepare for food.