Mutations in SOD1 cause structural changes in SOD1 that expose the Copper site to aberrant (different from normal) substrates, particularly hydrogen peroxide (to form hydroxyl radicals), and will also promote the copper-mediated catalysis of peroxynitrite damage to intracellular proteins (via nitration of tyrosine residues of target proteins- signalling cell death).
Abnormal Protein aggregation is a common feature of many neurodegenerative disorders including ALS. In ALS, aggregates are primarily found in motor neurons and glial cells. Several studies show SOD1 as a component of these aggregates and it has been shown that SOD1 has an increased propensity for aggregation.
Mitochondria show signs of swelling and dysfunction in early ALS. In sporadic ALS, defects of the electron transport chain have been found. Mutant SOD1 has also been found to directly disrupt mitochondrila function (SOD1 aggregates are found in the mitochondria too), possibly through disruption of the association between cytochrome C and the inner mitochondrial membrane. Mitochondrial dysfunction ultimately leads to the production of ROS and cell damage/DNA damage.
In motor neurons, most glutamate is cleared from the synapse by the glial glutamate transporter, EAAT2 (also known as GLT1). In sporadic ALS, glutamate levels are increased in the CSF, suggesting problems with glutamate handling. Glutamate transport is also markedly reduced, due to loss of EAAT2 (shown by reduced EAAT2 protein levels in mutant SOD1 mouse models) and selective inactivation of EAAT2 by mutant SOD1.
GluR2 and ALS
In most cells, AMPARs are tetramers of at least one GluR2 subunit and have low Ca permeability. The levels of mRNA for GluR2 in motor neurons is lower than that of other neurons. Lack of GluR2 accelerates motor neuron degeration and life span in SOD1 mutant mice and replacement of GluR2 will increase life span.
Growth Factor Deficiency
This is one of the possible non-SOD1 related pathophysiological mechanisms behind ALS. Targeted deletion of part of the VEGF gene causes motor pathology and features of ALS pathology (possible role of VEGF in ALS). This is reinforced by the fact that progression of motor neuron disease is delayed in SOD1 mutant mice after:
- Overexpression of VEGF
- ICV administration of VEGF
- IM delivery of VEGF-expressing lentiviral vectors
Other growth factors (IGF-1 and GDNF (Glial cell derived neurotrophic factor)) also have similar effects.
Role of Glial Cells
Glial cells seem to contribute to disease progression. Astrocytic inclusions are an early indicator of SOD1 mutant toxicity. Also, astrocytes expressing mutant SOD1 secrete factors that are toxic to motor neurons, e.g. proinflammatory cytokines and chemokines (e.g. TNF-alpha).
Defective Axonal Transport
Neurofilaments are the most common cytoskeletal protein in motor neurons and play a key role in axonal growth. Abnormal accumulation of neurofilaments in the soma and axons are hallmarks of ALS. Transgenic mice with mutations or overexpression of neurofilaments display motor neuron dysfunction. Mutant SOD1 mice have defective axonal transport.
Why is this selective for motor neurons?
One possibility is that motor neurons are more susceptible to excitotoxicity.
- Spinal motor neurons receive very strong glutaminergic input
- They express Ca(2+) permeable AMPA receptors
- They have low Ca(2+) buffering capacity