Amyotrophic lateral sclerosis is a progressively fatal motor neuron disease. ALS causes the degradation of motor neurons in the central nervous system and the neurons involved in voluntary movement. This results in paralysis.
ALS was first identified in 1930. There are two subtypes of ALS; familial ALS (FALS) and sporadic ALS (SALS).
FALS is hereditary and accounts for ____% of ALS cases. There are several subtypes of FALS:
ALS1 is the most common subtype of FALS. It is caused by a mutation to SOD1 on chromosome 21q22.1.
ALS2 is caused by a mutation of the ALS gene on chromosome 2q33 (REFERENCE). Symptoms of ALS type 2 manifest in early childhood or adolescence.
Lateral sclerosis occurs in the anterior and lateral columns of the spinal cord and cause axonal degeneration. During this degeneration, the Schwann cells break down the surrounding myelin sheath and causes fragmentation. The motor neurons that are lost are replaced by fibrous astrocytes (REFERENCE).
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Sclerosis will eventually occur in the primary and secondary motor cortices in the brain.
In typical ALS, the cranial nerves are not affected along with the posterior columns and spinocerebellar tracts of the spinal cord (REFERENCE).
Three genes have been linked to the development of FALS. Mutations in these genes are responsible for the detrimental effects of the disorder.
Superoxide dismutase 1 (SOD1) is a soluble homodimeric enzyme found throughout the body. SOD1 is encoded on the SOD gene found on chromosome 21, position 22.1. SOD1 is responsible for the removal of superoxide free radicals by binding to zinc and copper ions. Copper ions bind to SOD1 and are involved in free radical removal while SOD1 binds to zinc ions to promote dimerization and stability. This is an important biological function as free radicals can cause damage to surrounding cells. (REFERENCE).
Mutations of SOD1 have been linked to FALS. A4V is the most common mutation in ALS1 patients in the U.S. This mutation of the SOD1 gene involves a substitution of alanine with valine at codon 4. Studies have shown that mutations in the structure of the enzyme form aggregations located in the spinal cord which contribute to the detrimental effects of ALS (REFERENCE). Mutant SOD1 has an altered structure and cannot bind to copper and zinc properly. The protein may interact with other similar cellular components to cause damage (Tiwari, 2000).
Mutant SOD1 could also affect the transport of essential materials within neurons. Axonal transport is an essential in normal axon function. Mutant SOD1 may affect the motor protein dynein. In a normal neuron, dynein transports materials from the periphery to the soma. Dynein is activated by dynactin. The motor protein attaches and moves via axonal tubulin microtubules using ATP. A mutation in either dynein or dynactin affects retrograde transport and produces similar effects as seen in FALS (REFERENCE).
Tar DNA-binding protein (TARDBP) is a protein in human encoded on chromosome 1. TARDBP binds to TAR DNA and deactivates HIV-1 transcription (REFERENCE). When TARDBP is hyperphosphorylated, ubiquitinated and cleaved, it forms TDP-43. TDP-43 has been thought to be the major protein found in ALS and ubiquitin-positive frontotemporal dementia (FTD) (REFERENCE). TDP-43 is usually located in the nucleus although the mutated version of the protein is found in the cytosol. Accumulation of TDP-43 in the cytosol will lead to loss of cellular function and will result in ______. Ubiquitin-positive TDP-43 is a nuclear protein which binds to nucleic acids.
TDP-43 regulates nucleic acid transcription and splicing but may also play a role in apoptosis and cell division along with microRNA manufacture. Removal of TDP-43 from the nucleus would result in a disruption of DNA and RNA splicing and transcription which accounts for the increase of the protein in the cytosol (Arai et al, 2006).
TDP-43 accumulation has also been linked to frontotemporal lobar degeneration (FTLD). In FTLD, patients develop cognitive dysfunction and changes in behaviour as a result of atrophy in the frontal and temporal lobes. Ubiquitin-positive, tau and Î±-synuclein negative inclusions contain TDP-43 and research has shown that it affects regions such as the hippocampus, neocortex and spinal cord. It is suggested that TDP-43 may be the common link between FTLD and ALS (Neumann et al, 2006).
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Fused in sarcoma (FUS) is a protein which is encoded by the FUS gene on chromosome 16. The N-terminal region of the protein has a domain which activates transcription. The C-terminal region includes the RNA recognition motif (RRM), zinc finger domains and an Arg-Gly-Gly (RGG) rich region. The FUS protein binds to nucleic acids and transports between the nucleus and cytoplasm. FUS is involved in several stages of gene expression as it regulates transcription, pre-mRNA splicing and microRNA processing. FUS also transports mRNA to neuronal dendrites (REFERENCE).
FUS is normally located in the nucleus of the cell although studies have shown that pathological FUS inclusions are predominately found in the cytosol and inclusion bearing cells (REFERENCE). It is unknown how FUS inclusions are found in the cytosol and there are no other cell proteins found.
A mutation of the FUS gene has been linked to FALS as it represents 5% of all FALS cases (Strong et al. 2010). Mutations in the C-terminal region lead to aggregation of the protein in the cytosol. It is unknown if the aggregation of mutant FUS is caused by disrupted nuclear-cytoplasmic transport or other mutated proteins found in the cytosol. A post-mortem study by Vance and co-workers (2009) has shown that lower motor neurodegeneration is linked to FUS cytoplasmic inclusions.