Devastating 'founder effect' genetic disorder raced to defective mitochondria in cerebellar neurons

December 06, 2011

Defective mitochondria, the energy-producing powerhouses of the cell, trigger an inherited neurodegenerative disorder that first shows itself in toddlers just as they are beginning to walk, Canadian scientists reported at the American Society for Cell Biology Annual Meeting, Dec. 6, in Denver.

The disorder, Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS), was first identified in the late 1970s among the descendants of a small population of 17th century French immigrants who settled in the Charlevoix and the Saguenay River regions northeast of Quebec City.

At the ASCB meeting, a team of researchers at the Montreal Neurological Institute at McGill University and the Centre Hospitalier de l'Université Montréal (CHUM), reported that they had traced the cellular basis of ARSACS to disruptions in neuronal mitochondria, particularly in Purkinje cells in the cerebellum.

The identification of defective mitochondria as the cellular mechanism underlying ARSACS follows a series of discoveries that were made possible by the relatively high incidence (one in 1,500 to 2,000 in this Canadian population) of ARSACS and detailed genealogical records on this population.

In 2000, scientists pinpointed the genetic mutation responsible for the disease, and subsequently identified the massive 4,579 amino acid protein, named sacsin, coded by the ARSACS gene.

Over 100 separate mutations have been found in people diagnosed with ARSACS in Japan, Turkey, and across Western Europe.

The researchers, led by Peter McPherson, Ph.D., Paul Chapple, Ph.D., and Bernard Brais, M.D., Ph.D., developed a genetically modified mouse model that could not produce the normal sacsin protein.

The sacsin-knockout mice developed neurons with abnormally shaped and poorly functioning mitochondria, the organelles that act as energy-producing powerhouses in cells.

This disruption led to the eventual death of individual neurons within the Purkinje layer of the cerebellum. The same result occurred when the scientists repeated the experiment in a laboratory culture of neurons in which sacsin was knocked down by a lentiviral system driving inhibitory RNA.

McPherson said that at the cellular level, ARSACS is similar to such neurodegenerative diseases as Huntington's, Parkinson's, and Alzheimer's.

ARSACS has minimal effects on cognitive functions but instead concentrates its damage within the cerebellum, the center of muscle coordination at the base of the brain. The unsteadiness of gait, or ataxia, in children with ARSACS worsens, progressing through a growing list of difficulties with coordination, muscle wasting, uncontrolled eye movement, retinal streaks, peripheral neuropathy, and impaired speech. By the age of 40, most ARSACs patients must use wheelchairs.
-end-
CONTACT:

Peter S. McPherson, Ph.D.
514-398-7355
Peter.mcpherson@mcgill.ca

Anita Kar
514-398-3376
anita.kar@mcgill.ca

John Fleischman
513-929-4635 (direct-Eastern time)
513-706-0212 (cell)
jfleischman@ascb.org

Cathy Yarbrough
858-243-1814
sciencematter@yahoo.com

AUTHORS PRESENT:

Tuesday, Dec. 6 2 to 3:30 p.m. Session: Cell Death Presentation: 1821 Board: B748
Exhibit Halls: A/B/E/F This research was supported by the Fondation de l'Ataxie Charlevoix-Saguenay (http://www.arsacs.com) and Neuromuscular Research Partnership Program of Canadian Institutes of Health Research and UK Medical Research Council.

American Society for Cell Biology

Related Neurons Articles from Brightsurf:

Paying attention to the neurons behind our alertness
The neurons of layer 6 - the deepest layer of the cortex - were examined by researchers from the Okinawa Institute of Science and Technology Graduate University to uncover how they react to sensory stimulation in different behavioral states.

Trying to listen to the signal from neurons
Toyohashi University of Technology has developed a coaxial cable-inspired needle-electrode.

A mechanical way to stimulate neurons
Magnetic nanodiscs can be activated by an external magnetic field, providing a research tool for studying neural responses.

Extraordinary regeneration of neurons in zebrafish
Biologists from the University of Bayreuth have discovered a uniquely rapid form of regeneration in injured neurons and their function in the central nervous system of zebrafish.

Dopamine neurons mull over your options
Researchers at the University of Tsukuba have found that dopamine neurons in the brain can represent the decision-making process when making economic choices.

Neurons thrive even when malnourished
When animal, insect or human embryos grow in a malnourished environment, their developing nervous systems get first pick of any available nutrients so that new neurons can be made.

The first 3D map of the heart's neurons
An interdisciplinary research team establishes a new technological pipeline to build a 3D map of the neurons in the heart, revealing foundational insight into their role in heart attacks and other cardiac conditions.

Mapping the neurons of the rat heart in 3D
A team of researchers has developed a virtual 3D heart, digitally showcasing the heart's unique network of neurons for the first time.

How to put neurons into cages
Football-shaped microscale cages have been created using special laser technologies.

A molecule that directs neurons
A research team coordinated by the University of Trento studied a mass of brain cells, the habenula, linked to disorders like autism, schizophrenia and depression.

Read More: Neurons News and Neurons Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.