Tweezer-lying

Comprehensive List of Amyloidoses and Conditions Affected by Abnormal Protein Aggregation

Non-genetic diseases

Alzheimer’s disease (see also Familial Alzheimer’s disease)

Alzheimer’s disease (AD) is the most common neurodegenerative disease, affecting ~5.3 million Americans and ~36 million people worldwide. These numbers are predicted to triple by the middle of the 21st century. Currently, every 67 seconds, someone develops AD. Cost of care is estimated at $216 billion in the US alone. For more statistics about AD see the Facts and Figures page of the Alzheimer’s Association.

Two proteins aggregate and kill brain cells in AD—amyloid β-protein (Aβ) and tau, which form the pathological hallmarks of the disease—amyloid plaques and neurofibrillary tangles, respectively. The molecular tweezers have been shown to be effective against both Aβ and tau (Sinha et al., 2011, Attar et al., 2012, Sinha et al., 2012, Zheng et al., 2015).

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Age-related macular degeneration

Age-related macular degeneration (AMD) is a condition affecting mostly elderly people, causing loss of vision in the center of the visual field, the macula, because of damage to the retina. AMD is a major cause of blindness and visual impairment in people >50 years old. Approximately 10% of people 66–74 years old have findings of macular degeneration. The prevalence increases to 30% in people 75–85 years old. AMD begins with characteristic yellow deposits called drusen in the macula. These deposits have been found to contain toxic aggregates of amyloid β-protein (Aβ) and in animal models, therapy directed against Aβ was found to be protective against AMD. The molecular tweezers have not yet been tested for AMD, but their therapeutic action against Aβ in models of Alzheimer’s disease suggests that they will have a beneficial effect.

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Inclusion body myositis

Inclusion body myositis (IBM) is an inflammatory muscle disease characterized by slowly progressive weakness and muscle wasting. IBM affects nearly 15 million people worldwide and is the most common cause of inflammatory myopathy in people over age 50. One part of the disease mechanism is autoimmune and another part involves deposition of abnormally folded amyloid β-protein (Aβ) in the muscle cells. Experiments in mice have shown that therapy targeted against Aβ ameliorates the disease. The molecular tweezers have not yet been tested for IBM, but their action against Aβ suggests that they will have a therapeutic effect.

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Parkinson’s disease (see also Familial Parkinson’s Disease)

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. According to statistics available ~10 years ago, an estimated 6.3 million people had Parkinson’s worldwide. Though reliable current statistics are difficult to find, most resources suggest that PD affects 1 in 500 people. If the world’s population is about 7 billion, it means that approximately 14 million people have PD. The major risk factor for PD is age and incidence rises steeply with aging. Nonetheless, unlike AD, which very rarely afflicts people under age 60, PD strikes people in their 20’s, 30’s, and 40’s who struggle to work and raise families. In the US, estimated costs of care for PD are ~$25 billion per year.

In PD, a protein called α-synuclein forms toxic aggregates, which kill the nerve cells that produce dopamine and other nerve cells in multiple areas of the brain. Aggregated α-synuclein is found in hallmark lesions called Lewy bodies and Lewy neurites in the brain of people who have Parkinson’s disease. The molecular tweezers have been found to be effective against α-synuclein (Sinha et al., 2011, Prabhudesai et al., 2012, Acharya et al., 2014).

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Multiple system atrophy

Multiple system atrophy (MSA) is a neurodegenerative disease in which nerve cells degenerate in particular areas of the brain causing problems with movement, balance, and other autonomic functions of the body, such as bladder control and blood-pressure regulation. Some symptoms of MSA overlap with Parkinson’s disease. The prevalence of MSA is estimated at 4.6 per 100,000 people. Several rare diseases, including Shy–Drager Syndrome, olivopontocerebellar atrophy (OPCA), and striatonigral degeneration (SND) are classified under the umbrella of MSA. Almost 80% of patients are disabled within five years of onset of the motor symptoms, and only 20% survive past 12 years. Similarly to Parkinson’s disease, MSA is a synucleinopathy because a major pathological mechanism in MSA is abnormal aggregation of α-synuclein. The molecular tweezers currently are being tested in models of MSA. Their action against α-synuclein (Sinha et al., 2011Prabhudesai et al., 2012Acharya et al., 2014), suggests that they will be effective.

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Dementia with Lewy bodies

Dementia with Lewy bodies (DLB) also known as Lewy body dementiadiffuse Lewy body diseasecortical Lewy body diseasesenile dementia of Lewy type, and Lewy body variant of Alzheimer’s disease is a disease in which a mixture of symptoms akin to both Alzheimer’s and Parkinson’s diseases may be present. Sometimes, LBD is also referring to Parkinson’s disease dementia (PDD). LBD is estimated to account for between 10 to 25% of all dementia cases. DLB is classified as a synucleinopathy because a major pathological mechanism in MSA is abnormal aggregation of α-synuclein. The molecular tweezers have not been tested specifically for DLB but have been found to be effective against α-synuclein (Sinha et al., 2011Prabhudesai et al., 2012Acharya et al., 2014).

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Pure autonomic failure

Pure autonomic failure (PAF), also known as Bradbury–Eggleston syndrome or idiopathic orthostatic hypotension, is a rare disease that causes dizziness and fainting, visual disturbance, and neck pain. α-Synuclein aggregation, including formation of Lewy bodies and Lewy neurites, similar to Parkinson’s disease, are a characteristic of PAF, though unlike in Parkinson’s, they form in the parasympathetic nervous system. The molecular tweezers have not been tested specifically for PAF but have been found to be effective against α-synuclein (Sinha et al., 2011Prabhudesai et al., 2012Acharya et al., 2014).

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Type-2 diabetes mellitus

Type-2 diabetes is the most common form of diabetes, comprising ~90% of all cases and affecting over 200 million people around the world. It is a metabolic disorder that is characterized by high blood glucose, insulin resistance, and relative insulin deficiency. It is also the most prevalent amyloidosis. In type-2 diabetes, a small protein called islet amyloid polypeptide (IAPP) or amylin forms toxic aggregates that lead to destruction of β-cells in the pancreas—the cells that produce insulin. A synthetic analogue of human IAPP called pramlintide (brand name, Symlin), which does not aggregate, is used as therapy for type-2 diabetes. In addition, experiments in animal models directed against IAPP aggregation have found that such strategies have beneficial therapeutic effects. The molecular tweezers have been found to be effective against IAPP aggregation and toxicity (Sinha et al., 2011, Lopes et al., 2015).

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Frontotemporal dementia

Frontotemporal dementia (FTD), also called frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease characterized by severe degeneration of the frontotemporal lobe. It is the second most common cause of dementia after Alzheimer’s disease. Typical age of onset is between 45 to 65 years of age. The most common symptoms include significant changes in social and personal behavior, disinhibition, and a general blunting of emotions. FTD has been associated with pathologic aggregation of several proteins, including the microtubule-associated protein tau, which also aggregates into pathologic lesions in Alzheimer’s disease, and the proteins TDP-43 and FUS, whose aggregation is also involved in amyotrophic lateral sclerosis. The molecular tweezers have been shown to inhibit tau aggregation (Sinha et al., 2011) and to reduce neurofibrillary tangles (which are made of an abnormal form of tau) in a mouse model of Alzheimer’s disease (Attar et al., 2012). They have not yet been tested for inhibition of TDP-43 or FUS.

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Pick’s disease

Pick’s disease is a rare neurodegenerative disorder that causes progressive destruction of nerve cells in the brain. Symptoms include loss of speech (aphasia), personality changes, and dementia. The disease is fatal and most patients often die within 2 to 10 years. It is a specific pathology that is one of the causes of frontotemporal dementia, and similarly to frontotemporal dementia, Pick’s disease is a “tauopathy” characterized by build-up of abnormally aggregated tau in neurons in spherical lesions known as “Pick bodies”. The molecular tweezers have been shown to inhibit tau aggregation and to reduce neurofibrillary tangles (which are made of an abnormal form of tau) in a mouse model of Alzheimer’s disease (Attar et al., 2012).

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Corticobasal degeneration

Corticobasal degeneration (CBD) is a rare, progressive neurodegenerative disease involving the cerebral cortex and the basal ganglia. It is characterized by substantial movement disorder together with cognitive dysfunction. Though it is classified as a “Parkinson plus” syndrome, it is a tauopathy, which means that it is characterized by accumulation of abnormal tau aggregates in the brain. Clinical diagnosis of CBD is difficult because symptoms often overlap with those of Parkinson’s disease and progressive supranuclear palsy. The molecular tweezers have been shown to inhibit the aggregation of tau and to reduce neurofibrillary tangles (which are made of an abnormal form of tau) in a mouse model of Alzheimer’s disease (Attar et al., 2012).

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Progressive supranuclear palsy

Progressive supranuclear palsy (PSP), sometimes called Steele–Richardson–Olszewski syndrome, is a degenerative disease involving the gradual deterioration and neuron death in specific brain areas. The disease affects approximately 6 out of 100,000 people. Symptoms include loss of balance and other gait disturbances, dementia, slurred speech, difficulty swallowing, and difficulty moving the eyes. The average age of onset is 63 and survival from onset averages 7 years with a wide variance. Similarly to FTD, Pick’s disease, and corticobasal degeneration, PSP is a tauopathy characterized by neurofibrillary tangles made of abnormally aggregated tau. The molecular tweezers have been shown to inhibit the aggregation of tau and to reduce neurofibrillary tangles in a mouse model of Alzheimer’s disease (Attar et al., 2012).

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Amyotrophic lateral sclerosis (see also familial amyotrophic lateral sclerosis)

Amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease) is a devastating, progressive, neurodegenerative disease that causes severe disability and typically is fatal after 3 to 5 years. ALS is the most common adult motor-neuron disease with an incidence of ~2 in 100,000. The disease has no effective therapy and the mechanisms responsible for pathophysiology are not well understood. Mutations linked to familial ALS (see below) have been helpful in exploring the processes that cause the disease. The most studied ones are those in the gene that encodes the oxidative-stress-related enzyme SOD1. SOD1 has been found to form abnormal, toxic aggregates in patients with ALS. However, whether these aggregates cause the disease is still an open question. The molecular tweezers have been found to inhibit the aggregation of SOD1, to dissociate pre-existing aggregates of SOD1, and to improve the viability of motor neurons containing toxic mutants of SOD1. Currently, the molecular tweezers are being tested in a mouse model that has a mutant form of SOD1 and develops ALS-like disease.

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Senile systemic amyloidosis (see also familial amyloidotic polyneuropathy and familial amyloidotic cardiomyopathy)

Senile systemic amyloidosis (SSA) is a common age-related amyloidosis that involves abnormal accumulation and aggregation of the protein transthyretin in different tissues. Cardiac dysfunction typically is a predominant SSA symptom and, in turn, the disease is a common cause of heart failure in the elderly. The prevalence of SSA can reach 25% in people of age 85 or older. Currently, there is no treatment for SSA. A drug for familial amyloidotic polyneuropathy, a related genetic disease, was approved in Europe and may be effective against SSA too. The molecular tweezers have been found to inhibit the aggregation of transthyretin and to block its toxicity in cell culture (Sinha et al., 2011). In addition, the molecular tweezers showed reduction of TTR aggregation in a mouse model of familial amyloidotic polyneuropathy (Ferreira et al., 2014) with concomitant decrease in cell death, oxidative stress, and protein damage in the digestive and nervous systems, suggesting that they may be effective for SSA treatment.

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Primary amyloidosis

Primary amyloidosis, also called amyloid light-chain (AL) amyloidosis or primary systemic amyloidosis is the most common form of systemic amyloidosis. Typically, it occurs as a complication of multiple myeloma. Primary amyloidosis is a devastating disease in which a population of certain bone-marrow cells produces a mutant form of an antibody. The disease affects 1 in 100,000 people annually and the median survival after diagnosis is 3 years. Current treatment options are chemotherapy and bone-marrow transplantation. The molecular tweezers have been found to inhibit the aggregation of mutant antibodies in the test tube, suggesting that they may be effective for treatment of Primary amyloidosis.

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Dialysis-related amyloidosis

Dialysis-related amyloidosis (DRA) is a disabling disease characterized by accumulation and tissue deposition of amyloid fibrils consisting of the protein β2-microglobulin (β2m) in the bone and other tissues of patients with chronic kidney disease. The disease affects 20% of patients after 2 to 4 years of dialysis and nearly 100% after 13 to 15 years. In recent years, however, DRA prevalence has decreased with the use of high-flux biocompatible dialysis membranes, which provide improved clearance of β2m and are less likely to induce reactive inflammation. Nonetheless, hundreds of thousands of people still suffer from this debilitating disease every year. The molecular tweezers have been shown to inhibit effectively the aggregation of β2m in the test tube and to prevent the toxicity of β2m in cell culture (Sinha et al., 2011).

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Systemic (reactive) AA amyloidosis

Systemic (reactive) AA amyloidosis, also called simply AA amyloidosis is a form of amyloidosis, i.e. a disease characterized by the abnormal aggregation and deposition of insoluble protein in the extracellular space of various tissues and organs. In AA amyloidosis, the deposited protein is serum amyloid A (SAA), an “acute-phase” protein which is normally soluble and whose plasma concentration is highest during inflammation. AA amyloidosis is a rare disease, which accounts for about 3% of all systemic amyloidosis cases. It is associated with inflammation in a variety of diseases, including rheumatoid arthritis, inflammatory bowel disease, familial Mediterranean fever, tuberculosis, osteomyelitis, and bronchiectasis. The molecular tweezers have not yet been tested against SAA or AA amyloidosis.

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Prostatic amyloidosis

Prostatic amyloidosis is a rare condition in which amyloid is deposited in the prostate and lower genital/urinary tract. The amyloid in this condition tends to have diverse morphology and may be composed of transthyretin, β2-microglobulin, or both proteins. The clinical presentation of prostatic amyloidosis can be part of systemic amyloidosis (primary or secondary) and resemble a tumor of the prostate. The molecular tweezers have been shown to inhibit effectively the aggregation and toxicity of both transthyretin and β2-microglobulin in the test tube and in cell culture, respectively (Sinha et al., 2011). In addition, a recent study in a mouse model of transthyretin amyloidosis showed significantly reduced amyloid deposition, oxidative stress, and cell death in mice treated with a molecular tweezer relative to placebo-treated mice (Ferreira et al., 2014).

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Conjunctival amyloidosis

Conjunctival amyloidosis is a rare, localized disease that usually occurs in middle-aged adults. In conjunctival amyloidosis, amyloid made of currently unknown proteins is deposited in the conjunctiva—the membrane that covers the front of the eye and lines the inside of the eyelids. Symptoms include pain or droopy eyelids. There is currently no treatment for this condition. The molecular tweezers have not yet been tested against conjunctival amyloidosis, but their general mechanism of action suggests that they may be effective for treatment of this condition.

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Spinal cord injury and traumatic brain injury

Spinal cord injury (SCI) and traumatic brain injury (TBI) are conditions in which the spinal cord or the brain, respectively, suffer trauma, leading to symptoms that range from mild to very severe. Interestingly, in these conditions, certain proteins, including Aβ, tau, α-synuclein, and TDP-43 aggregate abnormally and form insoluble deposits in the affected tissue. It is not clear to what extent the abnormal protein aggregation and deposition contribute to the neuronal degeneration and loss in SCI and TBI, yet recent animal studies suggest that preventing the abnormal protein aggregation may help neurons to survive. The molecular tweezers have been found to inhibit synuclein aggregation in one such model, which resulted in increased neuronal survival.

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Chronic traumatic encephalopathy

Chronic traumatic encephalopathy (CTE) is a form of encephalopathy that is a progressive degenerative disease. It occurs in individuals with a history of multiple concussions and other forms of head injury. The disease was previously called dementia pugilistica (DP), as it was originally found in people with a history of boxing. CTE has been most commonly found in professional athletes who participate in American football, ice hockey, professional wrestling, or other contact sports and have experienced repetitive brain trauma. As found more generally in traumatic brain injury, part of the brain pathology found in CTE includes abnormally aggregated proteins, such as tau, TDP-43, and amyloid β-protein (Aβ). The molecular tweezers have been shown to inhibit the aggregation of Aβ and tau and to reduce amyloid plaques (predominantly made of Aβ) and neurofibrillary tangles (made of an abnormal form of tau) in a mouse model of Alzheimer’s disease (Attar et al., 2012) and therefore may be helpful in other diseases in which these proteins aggregate in the brain.

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Creutzfeldt–Jakob disease

CreutzfeldtJakob disease (CJD) is a degenerative neurological disorder that is incurable and invariably fatal. It is a human form of mad-cow disease (bovine spongiform encephalopathy or BSE) even though classic CJD is not related to BSE. However, variant Creutzfeldt–Jakob disease (vCJD) is believed to be caused in humans by ingestion of beef infected with BSE (see also, Gerstmann–Sträussler–Scheinker syndrome). The disease is caused by abnormal misfolding and aggregation of the prion protein. This abnormally misfolded form of the protein is infectious not only among individuals, but also among species. Therefore, eating a misfolded bovine prion can cause the disease in humans. The first symptom of CJD is rapidly progressive dementia, leading to memory loss, personality changes, and hallucinations. Sporadic (non-inherited) CJD can be fatal within months or even weeks. Most victims die six months after initial symptoms appear, often of pneumonia due to impaired coughing reflexes. A similar disease caused by misfolded prion is Kuru, a disease in Papua New Guinea, which likely was transmitted through cannibalism before it was banned in the 1950s. The molecular tweezers have not yet been tested for CJD, Kuru, or any prion-related disease.

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Insulin-related amyloidosis

Insulin-related amyloidosis, or injection-localized amyloidosis, is a rare condition that occurs in diabetic patients who do not alter the site of insulin injection. In such cases, insulin aggregates and forms subcutaneous amyloid at the site of the injection. The condition is not considered dangerous systemically and the amyloid can be removed surgically. The molecular tweezers have been shown to inhibit insulin aggregation and prevent its toxicity in cell culture (Sinha et al., 2011).

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Medullary carcinoma of the thyroid

In Medullary carcinoma of the thyroid or medullary thyroid cancer, the cancer is caused by abnormal division and proliferation of specific thyroid cells that produce the hormone calcitonin. Calcitonin is a small protein that undergoes abnormal aggregation in this disease and precipitates in the thyroid as amyloid. However, the amyloid is not considered dangerous and the main illness in this disease is the cancer itself. The molecular tweezers have been shown to inhibit the aggregation of calcitonin and prevent its toxicity in cell culture (Sinha et al., 2011).

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Isolated atrial amyloidosis

Isolated atrial amyloidosis is a form of amyloidosis affecting the atria (blood-collecting chambers) of the heart. It is caused by abnormal accumulation and aggregation of a small protein (peptide) called atrial natriuretic factor (ANF). The disease may play a role in the pathogenesis of atrial fibrillation and the main symptom is arrhythmia. The molecular tweezers have not yet been tested against ANF, but their general mechanism of action suggests that they may be effective for treatment of atrial amyloidosis.

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HIV infection

Human immunodeficiency virus (HIV) infection causes acquired immunodeficiency syndrome (AIDS). Semen is the main vehicle for the transmission of HIV. Semen may contain abnormal amyloid aggregates called SEVI (semen-derived enhancer of virus infection) made of the proteins PAP and SEM1/2, which enhance viral infectivity about 10 times. Therefore, inhibition of formation of these protein aggregates may reduce HIV infection. The molecular tweezers have been found to inhibit the formation of SEVI and block viral infection in cell culture.

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Preeclampsia

Preeclampsia is a pregnancy disorder of unknown cause and a leading contributor to morbidity and mortality of mothers and newborn babies. The only treatment for preeclampsia is delivery, which makes it the leading cause of induced pre-term birth. In July 2014, a new article reported a strong correlation between abnormal protein aggregation and preeclampsia. Among the proteins that were found to form abnormal aggregates are ceruloplasmin, immunoglobulin light chain (similar to primary amyloidosis), SERPINA1, albumin, interferon-inducible protein 6-16, and amyloid β-protein precursor (APP).

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Genetic diseases

Familial Alzheimer’s disease

(FAD) is very rare; less than 1% of AD patients have FAD. FAD Patients with FAD become sick at a relatively young age, typically, in their 40s or 50s, and the disease is more aggressive than sporadic AD. FAD can be caused by mutations in three different genes. The most common ones are in presenilin 1, which is involved in the production of amyloid β-protein (Aβ). Mutations in a counterpart gene called presenilin 2 have a similar impact. Both cause an increase in production of more toxic forms of Aβ. The third gene is the one producing the amyloid β-protein precursor itself, from which Aβ is produced. These mutations cause elevated production of Aβ or of Aβ forms that are more toxic and more prone to aggregation.

The molecular tweezers have been shown to be effective in animal models containing mutant forms of presenilin 1 and amyloid β-protein precursor and therefore are expected to be effective against FAD (Sinha et al., 2011, Attar et al., 2012).

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Familial Parkinson’s disease

(FPD) is very rare. It can be caused by mutations in several genes, and not in all cases these genes are directly related to abnormal protein aggregation. Mutations in the SNCA gene, which is responsible for production of α-synuclein, or multiplication of the SNCA gene, which lead to increased production of α-synuclein, cause FPD. The molecular tweezers have been found to be effective against α-synuclein (Sinha et al., 2011, Prabhudesai et al., 2012, Acharya et al., 2014) and therefore are expected to be beneficial for treatment of people with mutations or multiplications of the SNCA gene.

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Familial amyotrophic lateral sclerosis

(ALS, Lou Gehrig’s disease) is a devastating, progressive, neurodegenerative disease that causes severe disability and typically is fatal after 3 to 5 years. ALS is the most common adult motor-neuron disease with an incidence of ~2 in 100,000. The disease has no effective therapy and the mechanisms responsible for pathophysiology are not well understood. Mutations linked to familial ALS have been helpful in exploring the processes that cause the disease. Mutations in multiple genes have been found to be linked to ALS, including those that encode the oxidative-stress-related enzyme SOD1, RNA/DNA-binding proteins such as FUS and TDP-43, other proteins, including VCP, UBQLN2, and profilin 1, and recently, the orphan gene C9orf72, which is thought to account for many of the ALS cases that previously were considered sporadic. The proteins SOD1, FUS, TDP-43, and some fragments (peptides) derived from C9orf72 have been found to form abnormal, toxic aggregates in patients with ALS. However, whether these aggregates cause the disease is still an open question. The molecular tweezers have been found to inhibit the aggregation of SOD1, to dissociate pre-existing aggregates of SOD1, and to improve the viability of motor neurons containing toxic mutants of SOD1. Currently, the molecular tweezers are being tested in a mouse model that has a mutant form of SOD1 and develops ALS-like disease.

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Finnish hereditary systemic amyloidosis

Finnish hereditary systemic amyloidosis (also called familial amyloid polyneuropathy type IV or Meretoja amyloidosis) is a rare disease caused by mutations in the gene that encodes the protein gelsolin. Several hundred cases of the disease have been documented, mostly in Finland, but also in the USA, Denmark, and the Netherlands. The disease causes multiple pathologies, including in the brain, eye, and peripheral nervous system. The molecular tweezers have not yet been tested for Finnish hereditary systemic amyloidosis or against gelsolin, but their general mode of action suggests that they will be effective against this disease.

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Familial British dementia

Familial British dementia (FBD) is a rare disease caused by mutations in the BRI2 gene, leading to aggregation of the protein ABri. The disease causes symptoms similar to those of Alzheimer’s disease, but additional symptoms include spasticity and cerebellar ataxia. The average age of onset is 60 years. The molecular tweezers have not yet been tested for FBD or against ABri, but their general mode of action suggests that they will be effective against this disease.

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Familial Danish dementia

Familial Danish dementia (FDD) is a rare disease that similarly to FBD is caused by mutations in the BRI2 gene, leading to aggregation of another form of the protein called ADan. Symptoms include young-age cataracts, deafness, progressive ataxia, and dementia. The molecular tweezers have not yet been tested for FDD or against ADan, but their general mode of action suggests that they will be effective against this disease.

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Huntington’s disease

Huntington’s disease (HD) is a genetic neurodegenerative disorder that affects muscle coordination and leads to cognitive decline and psychiatric problems. It typically becomes noticeable in mid-adult life. HD is the most common genetic cause of abnormal, involuntary twitching movements called chorea. Physical symptoms can begin at any age from infancy to old age, but typically begin between 35 and 44 years of age. HD is a rare disease affecting approximately 4 people in a million. However, the chances that a person in a family with a history of the disease will get HD can be as high as 50%. The disease is caused by an autosomal dominant mutation in one of the two copies of a gene called huntingtin. The gene includes the genetic code for the protein huntingtin, which contains a long stretch of the amino acid glutamine. In normal people, the glutamine-repeat stretch contains up to 36 copies of this amino acid, whereas in affected individuals, the number of glutamines typically is over 40, and can be over 100. The longer the glutamine repeat is, the earlier the disease onset. Huntingtin containing a long glutamine repeat aggregates abnormally and deposits inside affected neurons, leading to dysfunction and death of these neurons. The molecular tweezers have been tested in cellular models of mutant huntingtin and showed beneficial effects, reducing the protein aggregation and increasing the cell survival.

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Spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17

In any of these types of spinocerebellar ataxias (SCA), a different protein with an expanded glutamine repeat undergoes abnormal aggregation and deposition in susceptible neurons (for more information, see http://en.wikipedia.org/wiki/Trinucleotide_repeat_disorder). These proteins include ataxin 1, ataxin 2, ataxin 3, which is responsible for Machado–Joseph disease, the Cav2.1 P/Q voltage-dependent calcium channel, ataxin 7, and TATA-binding protein. SCA is difficult to diagnose as there are over 60 different types of this disease. It is more accurately a group of genetic diseases characterized by slowly progressive incoordination of gait and often poor coordination of hands, speech, and eye movements. The molecular tweezers have not yet been tested for any type of SCA, but their general mode of action, and initial results obtained in a cellular model of Huntington’s disease, suggest that they may be effective at least against some forms of SCA.

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Dentatombral-pallidoluysian atrophy

Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, autosomal dominant spinocerebellar degeneration, which similarly to Huntington’s disease and the spinocerebellar atxias mentioned above, is caused by an expansion of a glutamine repeat sequence. In DRPLA, the glutamine repeat is in the protein atrophin-1. The disease is also known as Haw River Syndrome and Naito–Oyanagi disease. It is very rare except in Japan. Depending on the age of onset, DRPLA causes a variety of symptoms, including ataxia, dementia, seizures, and symptoms consistent with progressive myoclonus epilepsy. The molecular tweezers have not yet been tested for DRPLA, but their general mode of action, and initial results obtained in a cellular model of Huntington’s disease, suggests that they may be beneficial for this disease.

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Spinal and bulbar muscular atrophy

Spinal and bulbar muscular atrophy (SBMA), also known as spinobulbar muscular atrophy, bulbospinal atrophy, X-linked bulbospinal neuropathy (XBSN), X-linked spinal muscular atrophy type 1 (SMAX1), and Kennedy’s disease (KD), is a debilitating neurodegenerative disease resulting in muscle cramps and progressive weakness due to degeneration of motor neurons in the brain stem and spinal cord. Similarly to Huntington’s disease, the spinocerebellar atxias and dentatorubral-pallidoluysian atrophy, SBMA is caused by an expansion of a glutamine repeat sequence. In SBMA, the glutamine repeat is in the androgen receptor. The disease is linked to chromosome X, which means that it is inherited through the mother. The molecular tweezers have not yet been tested for SBMA, but their general mode of action and initial results obtained in a cellular model of Huntington’s disease suggest that they may be beneficial for this disease.

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Familial amyloidotic polyneuropathy

(FAP), also called transthyretin-related hereditary amyloidosistransthyretin amyloidosis, or Corino de Andrade’s disease, is caused by many different mutations in the protein transthyretin (TTR). FAP is a life-threatening disease, affecting predominantly the peripheral and autonomic nervous system. The disease has a wide geographic distribution with the largest populations in Portugal, Japan, and Sweden, and is estimated to affect ~5,000–10,000 patients worldwide. Current treatment options are liver transplantation or Vyndaqel (tafamidis), which has been approved in Europe but not in the US. The molecular tweezers have been found to inhibit the aggregation of TTR and to block its toxicity in cell culture (Sinha et al., 2011). In addition, the molecular tweezers showed reduction of TTR aggregation in a mouse model of FAP (Ferreira et al., 2014) with concomitant decrease in cell death, oxidative stress, and protein damage in the digestive and nervous systems, suggesting that they may be effective for treatment of FAP.

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Familial amyloidotic cardiomyopathy

Similarly to familial amyloidotic polyneuropathy, (FAC) is caused by different mutations in the protein transthyretin (TTR). FAC is also a life-threatening disease affecting mainly the heart, digestive system, and kidneys. The molecular tweezers have been found to inhibit the aggregation of transthyretin and to block its toxicity in cell culture (Sinha et al., 2011). In addition, the molecular tweezers showed reduction of TTR aggregation in a mouse model of familial amyloidotic polyneuropathy (Ferreira et al., 2014) with concomitant decrease in cell death, oxidative stress, and protein damage in the digestive and nervous systems, suggesting that they may be effective also for treatment of FAC.

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Familial oculoleptomeningel amyloidosis

Familial oculoleptomeningel amyloidosis is a rare disease caused by certain mutations in the protein transthyretin (TTR). Symptoms may include transient loss of consciousness, optic neuropathy, hearing loss, and gait disturbance. The disease is progressive and may be fatal. The molecular tweezers have been found to inhibit the aggregation of TTR and to block its toxicity in cell culture (Sinha et al., 2011). In addition, the molecular tweezers showed reduction of TTR aggregation in a mouse model of FAP (Ferreira et al., 2014) with concomitant decrease in cell death, oxidative stress, and protein damage in the digestive and nervous systems, suggesting that they may be effective also for treatment of familial oculoleptomeningel amyloidosis.

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Gerstmann–Sträussler–Scheinker syndrome

(GSS) is a very rare, usually familial, fatal neurodegenerative disease that affects patients from 20 to 60 years of age. Similarly to Creutzfeldt–Jakob disease (CJD), GSS is a transmissible spongiform encephalopathy caused by misfolding and aggregation of the prion protein. The exact incidence of GSS is unknown but is estimated to be between 1 to 10 per 100 million. Unlike CJD, which can be sporadic or acquired, as in the case of vCJD (see above), GSS is inherited and is found in only a few families in the world. Symptoms typically start with difficulty speaking and ataxia and then progress to dementia. The molecular tweezers have not yet been tested for GSS or any prion-related disease.

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Familial fatal insomnia

Fatal familial insomnia (FFI) is a very rare inherited autosomal dominant neurodegenerative disease cause by misfolding and aggregation of the prion protein. It is almost always caused by a mutation in the prion protein but can also develop spontaneously in patients with a non-inherited mutation variant called sporadic fatal insomnia (sFI). The mutated protein has been found in just 40 families worldwide, affecting about 100 people. The disease begins with insomnia and progresses to hallucinations, rapid weight loss, dementia, and death. The molecular tweezers have not yet been tested for FFI or any prion-related disease.

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Hereditary non-neuropathic systemic amyloidosis

Hereditary non-neuropathic systemic amyloidosis is a rare autosomal dominant disease in which amyloid deposition in the gastrointestinal tract is usually fatal by the fifth decade. The disease can be caused by several proteins that undergo pathologic aggregation. In some families, the disease is caused by mutations in the apolipoprotein AI gene, whereas in others the cause is mutations in apolipoprotein AII, lysozyme, or the α-chain of the protein fibrinogen A. This disease also sometimes is called OstertagOstertag Type A, or familial visceral amyloidosis. The molecular tweezers have not yet been tested against these proteins, but their mechanism of action suggests that they may be effective against aggregation of these proteins.

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Hereditary renal amyloidosis

Hereditary renal amyloidosis is a rare form of amyloidosis in which the affected organ is predominantly the kidney. The disease also sometimes is called OstertagOstertag Type B. Similarly to hereditary non-neuropathic systemic amyloidosis, hereditary renal amyloidosis can be caused by mutations in different proteins, including cystatin C, the α-chain of the protein fibrinogen A, or gelsolin. The mutant forms of these proteins form abnormal aggregates and deposits in the kidneys. The molecular tweezers have not yet been tested against these proteins, but their mechanism of action suggests that they may be effective against aggregation of these proteins.

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Familial Mediterranean fever

Familial Mediterranean fever (FMF), also known as Armenian disease, is a hereditary inflammatory disorder. Ninety per cent of patients have their first attack before age 18. Attacks develop over 2 to 4 hours and last 6–100 hours. Symptoms typically include fever and inflammation in the abdomen, joints, pelvis, chest, and/or skin. Due to the inflammatory process, serum amyloid A (SAA) aggregation and deposition is a common complication. The molecular tweezers have not yet been tested against SAA, but their mechanism of action suggests that they may be effective against aggregation of this protein and may be beneficial for FMF.

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Hereditary cerebral amyloid angiopathy

Hereditary cerebral amyloid angiopathy is a rare form of the more common, non-genetic disease cerebral amyloid angiopathy (CAA). CAA typically is associated with Alzheimer’s disease and is caused by accumulation of amyloid β-protein (Aβ) in the brain’s blood vessels. Some forms of CAA are caused by rare mutations in Aβ, whereas others can be caused by mutations in the protein cystatin C. The latter case is known as Icelandic hereditary cerebral hemorrhage with amyloidosis because it is caused by a mutation in cystatin C in Iceland. The deposition predisposes these blood vessels to failure, increasing the risk of a hemorrhagic stroke, which eventually often is the cause of death in these patients. The molecular tweezers have been shown to be effective in animal models containing mutations in Aβ (Sinha et al., 2011, Attar et al., 2012) and therefore are expected to be effective against hereditary CAA caused by Aβ aggregation and deposition. The molecular tweezers have not yet been tested against cystatin C.

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Chronic mental diseases

Chronic mental diseases (CMD), such as schizophrenia, are progressive genetic disorders characterized by delusions, paranoia and disorganized thinking. An imbalance in protein production versus clearance is a hallmark of dysfunctional neurons, leading to abnormal deposition of protein aggregates. The gene DISC1 (Disrupted-in-schizophrenia 1) gene is considered among the most promising candidate genes for causing CMD. The molecular tweezers have not yet been tested against DISC1, but their mechanism of action suggests that they may be effective against aggregation of this protein and may be beneficial for CMD.

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Autism spectrum disorder

Autism spectrum disorder (ASD) is a group of complex genetic conditions that affect an individual’s ability of socialization. Although the exact cause of the disorder has not been identified, the protein DISC1 has been reported to be associated with autism, in addition to its role in CMD (see above). DISC1 forms large insoluble aggregates that deplete the amount of the functional for of DISC1 in the cell. The molecular tweezers have not yet been tested against DISC1, but their mechanism of action suggests that they may be effective against aggregation of this protein and may be beneficial for ASD.

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Desmin-Related Myopathy

Desmin-Related Myopathy (DRM) is a neuromuscular disorder mainly associated with mutations in the desmin gene (DES) or in the α-B-crystallin gene.  Desmin is a protein that is critical for cytoskeletal organization and maintaining cardiomyocyte structure. α-B-crystallin is a chaperone protein that in heart cells maintains the correct structure of desmin. DRM is characterized by cytoplasmic aggregates of misfolded protein in inclusion bodies that reside in the perinuclear region of cardiomyocytes.

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