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| title | chunk | source | category | tags | date_saved | instance |
|---|---|---|---|---|---|---|
| ALS | 5/11 | https://en.wikipedia.org/wiki/ALS | reference | science, encyclopedia | 2026-05-05T11:04:10.701513+00:00 | kb-cron |
=== Environmental and other factors === The multi-step hypothesis suggests the disease is caused by some interaction between an individual's genetic risk factors and their cumulative lifetime of exposures to environmental factors, termed their exposome. The most consistent lifetime exposures associated with developing ALS (other than genetic mutations) include heavy metals (e.g. lead and mercury), chemicals (e.g. pesticides and solvents), electric shock, physical injury (including head injury), and smoking (in men more than women). Generally, the effect of each exposure is relatively small. For instance, an individual's lifetime risk of developing ALS might increase from "1 in 400" without exposure to between "1 in 300" and "1 in 200" if they were exposed to heavy metals. Some industries are heavily dependent upon the use or exposure to these environmental factors, which may increase employees' susceptibility. For example, agricultural tasks may involve as many as 5 such risk factors excluding workers' smoking habits. A range of other factors have weaker evidence supporting them and include participation in professional sports, having a lower body mass index, lower educational attainment, manual occupations, military service, exposure to beta-Methylamino-L-alanine (BMAA), and viral infections. Although some personality traits, such as openness, agreeableness and conscientiousness appear remarkably common among patients with ALS, it remains open whether personality can increase susceptibility to ALS directly. Instead, genetic factors giving rise to personality might simultaneously predispose people to develop ALS, or the above personality traits might underlie lifestyle choices which are in turn risk factors for ALS.
=== Viruses and retrotransposons === Many ALS patients have substantially increased expression of endogenous retroviruses (HERVs), which are remnants of infections that may have happened early in human evolution and remained integrated in the human genome. Similarly, about one in five people with ALS had high levels of retrotransposon activation and dysfunction of TDP-43, a protein which regulates human gene expression and inhibits activation of retroviral genes. Preliminary data suggest that antiviral therapy may be used to treat ALS and related diseases.
=== Autoimmune processes === Multiple studies have provided evidence suggesting that motor neurons in ALS patients may be susceptible to inflammatory responses driven by autoreactive immune cells. In 1991, researchers with Baylor College of Medicine found that antibodies could be used to target motor neurons in a mouse model, leading to limb weakness and other symptoms similar to ALS symptoms in humans. In 2025, researchers at Columbia University Medical School and La Jolla Institute for Immunology published the first study showing inflammatory T cells targeting a specific antigen (vulnerable site) on motor neurons in patients with ALS.
== Pathophysiology ==
=== Neuropathology === Upon examination at autopsy, 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. The defining feature of ALS 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 ALS with frontotemporal dementia, neurons throughout the frontal and temporal lobes of the brain die as well. The pathological hallmark of ALS 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 ALS, 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 or FUS protein, respectively. Prion-like propagation of misfolded proteins from cell to cell may explain why ALS starts in one area and spreads to others. The glymphatic system may also be involved in the pathogenesis of ALS.
=== Biochemistry ===