BACKGROUND

Amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease is a progressive neuromuscular condition
that is characterized by weakness, muscle wasting, fasciculation and increased reflexes
Two types of ALS
Patients eventually become disabled and incapable of taking care of themselves
Most people succumb to the illness within 5 years of onset 20% of ALS patients live for
more than 5 years after diagnosis
It was caused by As opposed to loss of SOD function being the primary cause of ALS, it is the gain of
toxic function in the mutant SOD enzymes rather than a loss of normal function
Caused by the degeneration of motor neurons of the brain and spinal cord
Initially presents with difficulty speaking or swallowing and leads to problems in gait or
dexterity that are a direct result of muscle weakness
Riluzole blocks TTX-sodium channels which has been associated with damaged neurons
Also inhibits kainate and NMDA receptors and stimulates the uptake of glutamate in the
brain

CU, ZN superoxide dismutase
Composed of a beta-barrel with 8 antiparallel beta strands arranged in a greek key motif where the
hydrophobic residues from the core of the barrel
The beta 4 loop forms the active site that is located at the hairpin turn
Tethers the dimer interface with the active site zinc
Has a stabilizing intervening disulfide bond
NEXT SLIDE
The superoxide (red) is a negatively charged that is dismuted by SOD1
Cu, Zn superoxide dismutase (SOD) is an abundant enzyme with cells that serves to keep cells safe
from metabolic waste found in the mitochondria
Catalyzes the conversion of the radical oxygen species superoxide (O2) to a molecular
oxygen (O2) and hydrogen peroxide (H2O2) which is then transformed into water and
oxygen by catalase
They form disulfide bonds, homodimerize, and pick up copper and zinc ions
In the oxidized state, one of the histidine ligands of the zinc ion will also ligate the Cu ion this is
referred to as the bridging histidine
When it is mutated, the stability of the enzyme significantly decreases there have been of 150
mutations in this gene that have been linked to familial type ALS and causes an accumulation of
protein aggregates in motor neurons;
In wild type SOD1 there have been implications in the onset of sporadic ALS
The denaturation curve will shift to the left
MITOCHONDRIA
Effect on neuronal mitochondria
Looking at the above pathway, the mutation of the SOD1 gene has a causative effect on
neuronal mitochondria
Accumulation of SOD1 involves the immature protein entering the mitochondria where it
will bind to metal ion to impair retrograde and anterograde axonal transport mechanisms
This results in an inhibition of the ability to properly control levels of calcium ions
and an increase in the concentration of calcium in the brain- impairing kinesin
functionality and inhibiting anterograde movement
Leads to a build up of protein oligomers
Mutation of SOD1 will also result in the stress of the endoplasmic reticulum and an accumulation of
misfolded or unfolded proteins causing cellular stress and eventual cell death