Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade.

Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidoses. In this review, we describe this field of science with particular reference to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. We list the proteins that are known to be deposited as amyloid or other types of aggregates in human tissues and the disorders with which they are associated, as well as the proteins that exploit the amyloid motif to play specific functional roles in humans. In addition, we summarize the genetic factors that have provided insight into the mechanisms of disease onset. We describe recent advances in our knowledge of the structures of amyloid fibrils and their oligomeric precursors and of the mechanisms by which they are formed and proliferate to generate cellular dysfunction. We show evidence that a complex proteostasis network actively combats protein aggregation and that such an efficient system can fail in some circumstances and give rise to disease. Finally, we anticipate the development of novel therapeutic strategies with which to prevent or treat these highly debilitating and currently incurable conditions.

The two-century journey of Parkinson disease research.

Since the first formal description of Parkinson disease (PD) two centuries ago, our understanding of this common neurodegenerative disorder has expanded at all levels of description, from the delineation of its clinical phenotype to the identification of its neuropathological features, neurochemical processes and genetic factors. Along the way, findings have led to novel hypotheses about how the disease develops and progresses, challenging our understanding of how neurodegenerative disorders wreak havoc on human health. In this Timeline article, I recount the fascinating 200-year journey of PD research.

Cell-based therapy for Parkinson's disease: A journey through decades toward the light side of the Force.

This review describes the history, development, and evolution of cell-based replacement therapy for Parkinson's disease (PD), from the first pioneering trials with fetal ventral midbrain progenitors to future trials using stem cells as well as reprogrammed cells. In the spirit of Tom Isaacs, the review takes parallels to the storyline of Star Wars, including the temptations from the dark side and the continuous fight for the light side of the Force. It is subdivided into headings based on the original movies, spanning from A New Hope to the Last Jedi.

What influences placebo and nocebo responses in Parkinson's disease?

Placebo treatment is associated with clinical improvements in many medical conditions, but is particularly important in Parkinson's disease because improvements are common, marked, and associated with objective neurochemical and neurophysiologic changes. This review will focus on the effect of the placebo in patients with PD and will discuss the pathophysiology, observed characteristics of motor and nonmotor placebo responses, and the patient and study characteristics that modify the placebo response. Similar to the placebo response, nocebo and lessebo effects alter clinical trial outcomes and impact conclusions. Whereas placebo-associated improvements are positively viewed by patients in clinical practice, they complicate clinical trials. The authors suggest strategies to reduce placebo effects during randomized placebo-controlled trials evaluating new therapies. © 2018 International Parkinson and Movement Disorder Society.

200 Years of Parkinson's disease: what have we learnt from James Parkinson?

2017 marks 200 years since James Parkinson's published his 'Essay on the Shaking Palsy'. Although now most famous for describing the condition that came to bear his name, Parkinson had a wide range of interests and his influence spread beyond medicine. In this review, we provide a biography of James Parkinson's remarkable life.Parkinson's paper not only comprehensively described the symptoms of Parkinson's disease (PD), but challenged his peers to better understand the pathophysiology of the PD. Key observation over the next 2 centuries, included the recognition of the link between the substantia nigra and PD and the discoveries of dopamine deficiency in patients with PD. We review the subsequent development of pharmacological and surgical therapies. Despite great progress over the last 200 years, Parkinson's hopes for a 'cure if employed early enough' or that 'some remedial process may ere long be discovered by which at least the progression of the disease may be stopped' remain apposite today and we reflect on the challenges ahead for the next century.

A Tribute to James Parkinson.

Exactly 200 years ago, the London surgeon-apothecary James Parkinson (1755-1824) published a 66-page-long booklet entitled An Essay on the Shaking Palsy, which contains the first clear clinical description of the shaking palsy or paralysis agitans, which we now refer to as Parkinson's disease. However, the value of this essay was not fully recognized during Parkinson's lifetime, which spanned the American Revolution, the French Revolution, and the Napoleonic Wars. James Parkinson was one of the most singular figures of his time and place. He was successively or concomitantly a virulent political activist, a popular medical writer, a scholarly medical contributor, a highly appreciated parish doctor, a prominent amateur chemist, a devoted madhouse doctor, and a renowned paleontologist. It is that branch of geology that brought Parkinson fame during his lifetime. He was an insatiable collector of fossils, minerals, and shells that came to form the core of the museum that he set out at his home in Shoreditch, England. These specimens are beautifully illustrated in his Organic Remains of a Former World (1804-1811), a three-volume treatise that rapidly became a standard paleontology textbook. Parkinson was a founding member of the Geological Society of London, and in recognition of his contribution to the nascent field of paleontology his name was given to many fossils, particularly ammonites (e.g. Nautilus parkinsoni). Hence, we owe much to Mr. Parkinson, the Paleontologist, as he used to be referred to after his death, for such a vast and multifaceted contribution to natural science and medicine.

Jean-Martin Charcot and Parkinson's disease: Teaching and teaching materials.

James Parkinson's 1817 seminal article was not well known in France until 1861, when Jean-Martin Charcot and his friend, Alfred Vulpian, published a detailed description in French of paralysis agitans. Their article provided clinical information to help French physicians make an accurate diagnosis by considering gait, shaking and rigidity as well as masked facies. As Charcot always had a strong desire to teach, this article describes his lessons on Parkinson's disease from 1868 to 1888, and also examines the teaching approach he used to pass on his latest findings to his students and colleagues. Charcot also used his role as thesis advisor to disseminate Parkinson's work, and seven of the theses he oversaw, which until now have been overlooked, reveal another facet of his teacher-student relationship. These dissertations provided Charcot with an opportunity to highlight what he had already identified concerning what is today referred to as 'Parkinson-plus syndromes'. Finally, this report concludes with an historical survey of the teaching materials that Paul Richer and Albert Londe developed for the Master at La Salpêtrière to provide him with visual documentation.

[Breve recorrido histórico de la enfermedad de Parkinson a 200 años de su descripción].

The original description of what currently is known as Parkinson's disease was published 200 years ago. During both these centuries, knowledge on symptomatology, pathophysiology, genetics and pharmaceutical and surgical treatment has significantly increased; however, this nosological entity continues to be of imprecise origin and progressive evolution. In the present review, the historical events that contributed to describe and improve the understanding of this disease are summarized.

La descripción original de lo que ahora conocemos como enfermedad de Parkinson fue publicada hace 200 años. Durante estos dos siglos, el conocimiento sobre la sintomatología, fisiopatología, genética, tratamiento farmacológico y quirúrgico se ha incrementado notablemente; no obstante, esta entidad nosológica continúa siendo de origen impreciso y de curso progresivo. En la presente revisión se resumen los acontecimientos históricos que contribuyeron a describir y mejorar el entendimiento de esta enfermedad.

Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy.

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

Disrupted identities: movement, mind, and memory in Parkinson's disease.

For the many clinicians au fait with the history of the clinical description of Parkinson's disease, they will be aware that the very earliest description of James Parkinson's "Shaking Palsy" in 1817 explicitly excluded the involvement of cognitive and emotional processes as manifestations of the disease. Within a short time following his treatise, it became all too clear to those in the field that Parkinson's disease is more than just a motor disorder, and as was aptly conceptualized by Paul McHugh, Professor of Psychiatry at Johns Hopkins Hospital from 1975 until 2001, Parkinson's disease is closer to being a "triadic disorder," encompassing motor, cognitive, and psychiatric elements (McHugh, 1989). Even this notion is now outdated, with the triad being accompanied by autonomic, pain, and other non-motor syndromes.

Chen Jingrun, China's famous mathematician: devastated by brain injuries on the doorstep to solving a fundamental mathematical puzzle.

Chen Jingrun (1933-1996), perhaps the most prodigious mathematician of his time, focused on the field of analytical number theory. His work on Waring's problem, Legendre's conjecture, and Goldbach's conjecture led to progress in analytical number theory in the form of "Chen's Theorem," which he published in 1966 and 1973. His early life was ravaged by the Second Sino-Japanese War and the Chinese Cultural Revolution. On the verge of solving Goldbach's conjecture in 1984, Chen was struck by a bicyclist while also bicycling and suffered severe brain trauma. During his hospitalization, he was also found to have Parkinson's disease. Chen suffered another serious brain concussion after a fall only a few months after recovering from the bicycle crash. With significant deficits, he remained hospitalized for several years without making progress while receiving modern Western medical therapies. In 1988 traditional Chinese medicine experts were called in to assist with his treatment. After a year of acupuncture and oxygen therapy, Chen could control his basic bowel and bladder functions, he could walk slowly, and his swallowing and speech improved. When Chen was unable to produce complex work or finish his final work on Goldbach's conjecture, his mathematical pursuits were taken up vigorously by his dedicated students. He was able to publish Youth Math, a mathematics book that became an inspiration in Chinese education. Although he died in 1996 at the age of 63 after surviving brutal political repression, being deprived of neurological function at the very peak of his genius, and having to be supported by his wife, Chen ironically became a symbol of dedication, perseverance, and motivation to his students and associates, to Chinese youth, to a nation, and to mathematicians and scientists worldwide.

The medical treatment of Parkinson disease from James Parkinson to George Cotzias.

It took exactly 150 years since James Parkinson's description in 1817 of the illness bearing his name until the development of effective therapy for this disorder, namely, the introduction of high-dosage levodopa by George Cotzias in 1967. During the first 50 years, no effective therapy was available, but neurologists reported using different agents, including metals. Then, around 1867, Charcot found solanaceous alkaloids to be somewhat helpful, and these became the accepted and popular therapy for the next 75 years. When basic scientists discovered that these alkaloids had central antimuscarinic activity, pharmaceutical chemists developed synthetic chemical agents that were equally effective, with possibly less adverse effects, and around 1950 these synthetic drugs became the standard medical therapy for Parkinson's disease (PD). The link between dopamine and PD did not take place until 1957, 140 years after Parkinson's Essay. The clue came from research on reserpine, a drug derived from the Rauwolfia plant that caused a sedative effect, now recognized as a drug-induced parkinsonian state. Initial investigations revealed that reserpine caused the release and depletion of serotonin stores in the brain. With that knowledge, Arvid Carlsson, a young pharmacologist in Sweden, decided to explore the possibility that reserpine might also affect brain catecholamines. In his now famous, elegant, and simple experiment, he showed that injecting l-dopa, the precursor of catecholamines, alleviated the reserpine-induced parkinsonian state in animals, whereas the precursor of serotonin failed to do so. Carlsson then developed a highly sensitive assay to measure dopamine, and his lab found that dopamine is selectively present in high concentrations in the striatum and that administered l-dopa could restore the dopamine depleted by reserpine. Carlsson postulated that all these findings implicate dopamine in motor disorders. Oleh Hornykiewicz, a young pharmacologist in Vienna, on being aware of the regional localization of brain dopamine, decided to measure it in the brains of people who had PD and postencephalitic parkinsonism. In 1960, he reported finding markedly depleted dopamine in the striatum in these conditions. Immediately after, Hornykiewicz teamed up with the geriatrician, Walther Birkmayer, to inject small doses of l-dopa intravenously (IV) into PD patients. They found benefit and pursued this treatment, but the gastrointestinal side effects limited the dosage, and many neurologists were doubtful that the effects from l-dopa were any better than those with antimuscarinic agents. A number of neurologists tested such low doses of IV l-dopa and even higher oral dosages, but without showing any dramatic benefit, not better than the antimuscarinics. Some of these studies were small, controlled trials. This general lack of efficacy with l-dopa prevailed, and neurologists were discouraged about l-dopa until 1967, when George C. Cotzias, a neuropharmacologist in New York, reported his results. He thought that PD may be result from the loss of neuromelanin in the substantia nigra, and he decided to try to replenish the depleted neuromelanin. Among the agents he tried was dl-dopa. He wisely began with low oral doses and increased the dosage slowly and steadily, thereby limiting the gastrointestinal complication. He also treated his patients for a long duration, months in a government-supported hospital. In the accompanying videotape of an interview Cotzias gave in 1970, he describes much of his success to be able to observe his patients over months while building up the dosage very slowly and observe for signs of toxicity. When higher doses, usually over 12 g/day, were reached, dramatic antiparkinsonian effects were observed, and a revolutionary new treatment for PD was established.

Four pioneers of L-dopa treatment: Arvid Carlsson, Oleh Hornykiewicz, George Cotzias, and Melvin Yahr.

Four individuals stand out as pioneers of the early work that led to levodopa becoming a revolutionary new treatment for Parkinson's disease: Arvid Carlsson, Oleh Hornykiewicz, George C. Cotzias, and Melvin D. Yahr. All four were MDs. The first three had extra training in pharmacology, and in fact did their research in pharmacology. The fourth was a clinical neurologist, the only one in this group with those credentials. The story starts with Carlsson, who became interested in studying the mechanism of reserpine's sedative effect, now recognized as a drug-induced parkinsonian state. A key experiment in 1957 showed that levodopa (l-dopa) could alleviate the immobility induced by reserpine in animals. Carlsson then showed that reserpine depleted brain dopamine, and that l-dopa restored it. Carlsson developed a sensitive fluorescent technique to measure dopamine levels, and his laboratory also showed the distribution of dopamine in animal brain to be highest in the striatum. Within a year, Carlsson postulated that dopamine appears to play a role in motor function. His proposal that dopamine serves as a neurotransmitter in brain was met with much skepticism, but he persisted and continued to study brain dopamine, eventually leading to being awarded the Nobel Prize in Medicine in 2000. Hornykiewicz also went into pharmacology research after graduating from medical school. Fortuitously, his assigned first project was on the blood pressure effects of dopamine, recognized as a precursor of norepinephrine. When he completed his postdoctoral studies, Carlsson's work on the reserpinized animal and on the regional distribution of brain dopamine was published. This inspired Hornykiewicz to determine dopamine levels in patients with Parkinson's disease. He obtained postmortem material, and his 1960 paper showed a marked depletion of dopamine in the striatum in this disorder. He went on in subsequent papers to correlate severity of parkinsonian features with the amount of striatal dopamine depletion. In the meantime, after his discovery of low dopamine in brains of patients with Parkinson's disease, Hornykiewicz persuaded Walther Birkmayer to inject l-dopa into patients. They reported success and continued this treatment, usually combining it with the use of a monoamine oxidase inhibitor. However, the response was limited in duration, and subsequent trials by others were not achieving similar success, and many failed to find any benefit. The fulfilment of the l-dopa story stemmed from the hypothesis held by Cotzias that Parkinson's disease was caused by loss of brain neuromelanin in the substantia nigra. Although Cotzias's research had been in pharmacology, he also headed a clinical pharmacology research group at a federal laboratory on Long Island, New York, USA. He decided to try to restore this pigment in patients, not animals, and one of the three drugs he tried was d,l-dopa. As reported in his 1967 article, d,l-dopa proved to be dramatically successful in reversing the symptoms, but at extremely high dosages and with considerable hematologic adverse effects. Cotzias immediately tested l-dopa and found the same benefit with half the dosage and without the hematologic problems. Yahr was a clinical neurologist who had been treating patients with PD with available therapy and also headed a federally financed research group investigating the disorder. Always on the lookout for potential new treatments, he was initially skeptical about l-dopa when studies with low doses were being reported. Seeing videos of patients presented by Cotzias, however, he realized that the results needed confirmation through a double-blind controlled clinical trial. He proceeded to develop and execute such a trial with l-dopa, duplicating Cotzias's success. Both Cotzias and Yahr had encountered motor fluctuations and dyskinesias, but the amelioration of bradykinesia, rigidity, and tremor was so pronounced that these adverse effects did not prevent regulatory approval of l-dopa, and almost 50 years later l-dopa remains the most effective pharmacologic agent for treating Parkinson's disease. This article relates the personal stories of these four pioneers and how they achieved their success.

Parkinson's disease and the skin.

The concept that the skin is a mirror of Parkinson's disease dates to the start of the last century. Despite dermatological disorders being recognised as a common non-motor symptom of Parkinson's disease, they are often overlooked. This article reviews the various skin disorders seen in Parkinson's disease and addresses the other dermatological questions that are frequently raised by those attending Parkinson's disease clinics.

Frederic Lewy: how the two World Wars changed his life, work, and name.

In 1912, Friedrich Lewy described the inclusion bodies present in Parkinson disease and in Lewy body dementia. Throughout his life, Lewy fought in two wars - on opposite sides. He was born in Berlin in a Jewish family, and served in the German Army in World War I. In the following years, on many occasions he had to change his line of research due to Nazi persecution. Lewy became a naturalized American, changed his name to Frederic Henry Lewey, and served in the US Army as a lieutenant colonel. Lewy died in 1950 and never used the famous eponym in his papers.

Em 1912, Friedrich Lewy descreveu os corpos de inclusão presentes na doença de Parkinson e na demência com corpos de Lewy. Ao longo sua vida, Lewy lutou em duas guerras, em lados opostos. Ele nasceu em Berlin em uma família de origem judaica e serviu no Exército alemão na Primeira Guerra Mundial. Nos anos seguintes, passou muitas vezes teve de mudar sua linha de pesquisa devido à perseguição Nazista. Lewy naturalizou-se americano, mudou seu nome para Frederic Henry Lewey, e serviu no Exército americano como tenente-coronel. Lewy morreu em 1950 e nunca usou o famoso epônimo em seus artigos.

The history of parkinsonism: descriptions in ancient Indian medical literature.

The clinical syndrome of parkinsonism was identified in ancient India even before the period of Christ and was treated methodically. The earliest reference to bradykinesia dates to 600 bc. Evidences prove that as early as 300 bc, Charaka proposed a coherent picture of parkinsonism by describing tremor, rigidity, bradykinesia, and gait disturbances as its components. The scenario was further developed by Madhava, Vagbhata, and Dalhana all through history. The 15th-century classic "Bhasava rajyam" introduced the term kampavata, which may be regarded as an ayurvedic analogue of parkinsonism. The pathogenesis of kampavata centered on the concept of imbalance in the vata factor, which controls psychomotor activities. The essential element in therapy was the administration of powdered seed of Mucuna pruriens, or atmagupta, which as per reports, contains 4%-6% of levodopa. In addition to proving the existence and identification of parkinsonism in ancient India, the study points to the significance of ancient Indian Sanskrit works in medical history.