Neuropathology The defining feature of<unk>  is the death of both upper motor neurons (located in the motor cortex of the brain) and lower motor neurons (located in the brainstem and spinal cord). In<unk>  with frontotemporal dementia, neurons throughout the frontal and temporal lobes of the brain die as well. The pathological hallmark of<unk>  is the presence of inclusion bodies (abnormal aggregations of protein) known as Bunina bodies in the cytoplasm of motor neurons. In about 97% of people with<unk> , the main component of the inclusion bodies is TDP-43 protein; however, in those with SOD1 or FUS mutations, the main component of the inclusion bodies is SOD1 protein or FUS protein, respectively. The gross pathology of<unk> , which are features of the disease that can be seen with the naked eye, include skeletal muscle atrophy, motor cortex atrophy, sclerosis of the corticospinal and corticobulbar tracts, thinning of the hypoglossal nerves (which control the tongue), and thinning of the anterior roots of the spinal cord. Aside from the death of motor neurons, two other characteristics common to most<unk>  variants are focal initial pathology, meaning that symptoms start in a single spinal cord region, and progressive continuous spread, meaning that symptoms spread to additional regions over time. Prion-like propagation of misfolded proteins from cell to cell may explain why<unk>  starts in one area and spreads to others. The glymphatic system may<unk> o be involved in the pathogenesis of<unk> . Biochemistry This figure shows ten proposed disease mechanisms for<unk>  and the genes associated with them. It is still not fully understood why neurons die in<unk> , but this neurodegeneration is thought to involve many different cellular and molecular processes. The genes known to be involved in<unk>  can be grouped into three general categories based on their normal function: protein degradation, the cytoskeleton, and RNA processing. Mutant SOD1 protein forms intracellular aggregations that inhibit protein degradation. Cytoplasmic aggregations of wild-type (normal) SOD1 protein are common in sporadic<unk> . It is thought that misfolded mutant SOD1 can cause misfolding and aggregation of wild-type SOD1 in neighboring neurons in a prion-like manner. Other protein degradation genes that can cause<unk>  when mutated include VCP, OPTN, TBK1, and SQSTM1. Three genes implicated in<unk>  that are important for maintaining the cytoskeleton and for axonal transport include DCTN1, PFN1, and TUBA4A. There are a number of<unk>  genes that encode for RNA-binding proteins. The first to be discovered was TDP-43 protein, a nuclear protein that aggregates in the cytoplasm of motor neurons in almost all cases of<unk> ; however, mutations in TARDBP, the gene that codes for TDP-43, are a rare cause of<unk> . FUS codes for FUS, another RNA-binding protein with a similar function to TDP-43, which can cause<unk>  when mutated. It is thought that mutations in TARDBP and FUS increase the binding affinity of the low-complexity domain, causing their respective proteins to aggregate in the cytoplasm. Once these mutant RNA-binding proteins are misfolded and aggregated, they may be able to misfold normal protein both within and between cells in a prion-like manner. This<unk> o leads to decreased levels of RNA-binding protein in the nucleus, which may mean that their target RNA transcripts do not undergo the normal processing. Other RNA metabolism genes associated with<unk>  include ANG, SETX, and MATR3. C9orf72 is the most commonly mutated gene in<unk>  and causes motor neuron death through a number of mechanisms. The pathogenic mutation is a hexanucleotide repeat expansion (a series of six nucleotides repeated over and over); people with up to 30 repeats are considered normal, while people with hundreds or thousands of repeats can have familial<unk> , frontotemporal dementia, or sometimes sporadic<unk> . The three mechanisms of disease associated with these C9orf72 repeats are deposition of RNA transcripts in the nucleus, translation of the RNA into toxic dipeptide repeat proteins in the cytoplasm, and decreased levels of the normal C9orf72 protein. Mitochondrial bioenergetic dysfunction leading to dysfunctional motor neuron axonal homeostasis (reduced axonal length and fast axonal transport of mitochondrial cargo) has been shown to occur in C9orf72-ALS using human induced pluripotent stem cell (iPSC) technologies coupled with CRISPR/Cas9 gene-editing, and human post-mortem spinal cord tissue examination. Excitotoxicity, or nerve cell death caused by high levels of intracellular calcium due to excessive stimulation by the excitatory neurotransmitter glutamate, is a mechanism thought to be common to all forms of<unk> . Motor neurons are more sensitive to excitotoxicity than other types of neurons because they have a lower calcium-buffering capacity and a type of glutamate receptor (the AMPA receptor) that is more permeable to calcium. In<unk> , there are decreased levels of excitatory amino acid transporter 2 (EAAT2), which is the main transporter that removes glutamate from the synapse; this leads to increased synaptic glutamate levels and excitotoxicity. Riluzole, a drug that modestly prolongs survival in<unk> , inhibits glutamate release from pre-synaptic neurons; however, it is unclear if this mechanism is responsible for its therapeutic effect.
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