When neurons degenerate…
Be it tasting your favorite wine, admiring a Van Gogh painting, listening to music, or smelling the perfume of your beloved, it is all mediated by the nervous system. The nervous system controls the functioning of all organs of our body. The motor system is essential for voluntary movements, and the sense of touch is conveyed by the sensory nervous system. As a consequence, nervous system dysfunction, as is the case in neurological disorders, can jeopardize one or several body functions.
In particular, neurodegenerative disorders can have devastating effects on the quality of life, and are often fatal. These disorders typically strike adult or adolescent people, are progressive in nature, and are incurable. Despite the high incidence of neurodegeneration and its increasing medical significance, our present understanding of the molecular pathogenesis of these diseases is still quite incomplete.
In our lab, we seek to unravel the molecular pathogenesis of the motor neurodegenerative disorder ALS, and of Charcot-Marie-Tooth disease, a peripheral motor and sensory neuropathy. To this purpose, we combine the power of Drosophila and mouse genetics with novel disruptive technologies, including the latest sequencing and imaging technologies, as well as in vivo cell-type-specific labeling of nascent proteomes by non-canonical amino acid tagging (NCAT).
Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder, characterized by the selective loss of both upper and lower motor neurons. This results in progressive muscle atrophy, weakness and fasciculation, as well as spasticity. In the United States, ALS is commonly known as Lou Gehrig’s disease, named after the famous baseball player in the 1920s and 1930s, who succumbed to the disease at age 38. ALS inevitably results in death, usually due to respiratory insufficiency, within 3 to 5 years after diagnosis. Apart from Lou Gehrig, other famous ALS victims include the Russian composer Dmitri Shostakovich, the Chinese military and political leader Mao Zedong, and the jazz composer and bassist Charles Mingus. Probably the most famous victim of this devastating disease is Stephen Hawking, English theoretical physicist and cosmologist. Unlike most ALS patients, Hawking suffers from a markedly mild form of the disease – he has been living with ALS for more than 40 years. Nevertheless, he cannot walk, talk, swallow, breathe easily, and he has difficulty in holding up his head. Still, one has to admire his attitude: “I have been lucky, that my condition has progressed more slowly than is often the case. But it shows that one need not lose hope.”
Charcot-Marie-Tooth disease (CMT) – also known as hereditary motor and sensory neuropathy (HMSN) – is the most common inherited neuromuscular disorder, characterized by length-dependent degeneration of peripheral motor and sensory nerves. This results in distal muscle wasting and weakness, sensory loss, reduced tendon reflexes and foot deformities. CMT is named after the French neurologists Jean-Martin Charcot and Pierre Marie, and the British neurologist Howard Henry Tooth, who were the first to describe the disease in 1886. Traditionally, CMT is divided into 2 major clinical entities: demyelinating forms (CMT1), in which nerve conduction velocities (NCVs) are severely reduced, and axonal forms (CMT2), in which NCVs are normal or slightly reduced. More recently, a third class has been added, dominant intermediate CMT (DI-CMT), which is characterized by intermediate NCVs and histological evidence of both axonal degeneration and demyelinating features.
Keywords: neurodegeneration, motor neuron, sensory neuron, ALS, CMT, tRNA synthetase, mRNA translation, RNA biogenesis, FUS.