Inherited neurodegenerative diseases

Neurological Examination ◽

Genetic Heterogeneity ◽

Molecular Pathology ◽

Regulatory Protein ◽

Top Down ◽

Irreversible Nature

Many disorders of the nervous system, especially the degenerative conditions, have a genetic basis, which is usually due to a mutated gene resulting in decreased production of a critical structural or regulatory protein. Inherited neurodegenerative disorders present an enormous challenge because of the complexity of the nervous system, the broad clinical and genetic heterogeneity characteristic of these diseases, and the progressive and generally irreversible nature of their neuropathology. This chapter reviews and provides a guideline for inherited neurodegenerative disease. It is organized in a manner that a good neurological examination would be organized (i.e. systemic disorders followed by neurological disorders), discussed in a top-down manner (i.e. from cortex to muscle). Discussion of individual disorders starts with the molecular genetics, followed by molecular pathology, histology, clinical features, investigational findings, and management.

Inherited neurodegenerative diseases

Oxford Textbook of Medicine ◽

10.1093/med/9780199204854.003.02417 ◽

2010 ◽

pp. 5096-5133

Author(s):

Edwin H. Kolodny ◽

Swati Sathe

Keyword(s):

Nervous System ◽

Family History ◽

Genetic Heterogeneity ◽

Regulatory Protein ◽

Neurological Signs ◽

System P ◽

Slow Progression ◽

Special Part ◽

Irreversible Nature

Case History—A 54 yr old man presenting with intermittent focal neurological signs. Many nervous system disorders have a genetic basis, but may be difficult to diagnose because of nonspecific signs, slow progression, and lack of any family history. Neurodegenerative disorders present an enormous challenge because of the complexity of the nervous system, the broad clinical and genetic heterogeneity characteristic of these diseases, and the progressive and generally irreversible nature of their neuropathology. A mutated gene is generally at fault, resulting in decreased production of a structural or regulatory protein important for the development or normal functioning of a special part of the nervous system....

Immunotherapy for Neurodegenerative Disorders

10.1093/med/9780190233563.003.0017 ◽

2016 ◽

Author(s):

David Morgan

Keyword(s):

At Risk ◽

Health Concern ◽

Cultured Neurons ◽

Preclinical Data ◽

Age Related ◽

The World ◽

Disease Modifying

Neurodegenerative diseases are a growing health concern through the world as gains in longevity result in an increased population at risk of these age-related disorders. Unfortunately no disease modifying treatments exist for these disorders. Over the last three decades enormous insights have been gained into the causes of these disorders. One approach to treating these diseases is to direct immunotherapy against the misfolded proteins that accumulate within the brains of those with neurodegenerative disease in an attempt to clear the accumulating proteins and slow or prevent expression of the disease. This chapter summarizes the recent (and frustrating) experience with anti-Aβ‎ immunotherapy to treat mild to moderate Alzheimer’s disease, and holds hope that newer generation antibodies and treating presymptomatic disease will have greater impact. In addition, it reviews the preclinical data regarding approaches to treating tau, synuclein, and prion disorders, all of which demonstrate consistent effects in mice and cultured neurons.

Modulation of Neuroinflammation by the Gut Microbiota in Prion and Prion-Like Diseases

Pathogens ◽

10.3390/pathogens10070887 ◽

2021 ◽

Vol 10 (7) ◽

pp. 887

Author(s):

Josephine Trichka ◽

Wen-Quan Zou

Keyword(s):

Nervous System ◽

Gut Microbiota ◽

Peripheral Nervous System ◽

Brain Parenchyma ◽

Therapeutic Approaches ◽

Microbial Metabolite ◽

The Past

The process of neuroinflammation contributes to the pathogenic mechanism of many neurodegenerative diseases. The deleterious attributes of neuroinflammation involve aberrant and uncontrolled activation of glia, which can result in damage to proximal brain parenchyma. Failure to distinguish self from non-self, as well as leukocyte reaction to aggregation and accumulation of proteins in the CNS, are the primary mechanisms by which neuroinflammation is initiated. While processes local to the CNS may instigate neurodegenerative disease, the existence or dysregulation of systemic homeostasis can also serve to improve or worsen CNS pathologies, respectively. One fundamental component of systemic homeostasis is the gut microbiota, which communicates with the CNS via microbial metabolite production, the peripheral nervous system, and regulation of tryptophan metabolism. Over the past 10–15 years, research focused on the microbiota–gut–brain axis has culminated in the discovery that dysbiosis, or an imbalance between commensal and pathogenic gut bacteria, can promote CNS pathologies. Conversely, a properly regulated and well-balanced microbiome supports CNS homeostasis and reduces the incidence and extent of pathogenic neuroinflammation. This review will discuss the role of the gut microbiota in exacerbating or alleviating neuroinflammation in neurodegenerative diseases, and potential microbiota-based therapeutic approaches to reduce pathology in diseased states.

Molecular mechanisms of proteinopathies across neurodegenerative disease: a review

Neurological Research and Practice ◽

10.1186/s42466-019-0039-8 ◽

2019 ◽

Vol 1 (1) ◽

Cited By ~ 3

Author(s):

Alexander P. Marsh

Keyword(s):

Protein Misfolding ◽

Molecular Mechanisms ◽

Current Data ◽

Main Body ◽

Molecular Events ◽

Underlying Pathology

Abstract Background Although there is a range of different symptoms across neurodegenerative diseases, they have been noted to have common pathogenic features. An archetypal feature shared between these diseases is protein misfolding; however, the mechanism behind the proteins abnormalities is still under investigation. There is an emerging hypothesis in the literature that the mechanisms that lead to protein misfolding may be shared across neurodegenerative processes, suggesting a common underlying pathology. Main body This review discusses the literature to date of the shared features of protein misfolding, failures in proteostasis, and potential propagation pathways across the main neurodegenerative disorders. Conclusion The current data suggests, despite overarching processes being shared, that the molecular events implicated in protein pathology are distinct across common neurodegenerative disorders.

Peripheral Glycolysis in Neurodegenerative Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21238924 ◽

2020 ◽

Vol 21 (23) ◽

pp. 8924 ◽

Cited By ~ 1

Author(s):

Simon M. Bell ◽

Toby Burgess ◽

James Lee ◽

Daniel J. Blackburn ◽

Scott P. Allen ◽

...

Keyword(s):

Nervous System ◽

Blood Cells ◽

Large Scale ◽

White Blood Cells ◽

Peripheral Cells ◽

Multiple Patients ◽

Brain And Spinal Cord ◽

Lateral Sclerosis

Neurodegenerative diseases are a group of nervous system conditions characterised pathologically by the abnormal deposition of protein throughout the brain and spinal cord. One common pathophysiological change seen in all neurodegenerative disease is a change to the metabolic function of nervous system and peripheral cells. Glycolysis is the conversion of glucose to pyruvate or lactate which results in the generation of ATP and has been shown to be abnormal in peripheral cells in Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis. Changes to the glycolytic pathway are seen early in neurodegenerative disease and highlight how in multiple neurodegenerative conditions pathology is not always confined to the nervous system. In this paper, we review the abnormalities described in glycolysis in the three most common neurodegenerative diseases. We show that in all three diseases glycolytic changes are seen in fibroblasts, and red blood cells, and that liver, kidney, muscle and white blood cells have abnormal glycolysis in certain diseases. We highlight there is potential for peripheral glycolysis to be developed into multiple types of disease biomarker, but large-scale bio sampling and deciphering how glycolysis is inherently altered in neurodegenerative disease in multiple patients’ needs to be accomplished first to meet this aim.

Hsp70 and Its Molecular Role in Nervous System Diseases

Biochemistry Research International ◽

10.1155/2011/618127 ◽

2011 ◽

Vol 2011 ◽

pp. 1-18 ◽

Cited By ~ 112

Author(s):

Giuseppina Turturici ◽

Gabriella Sconzo ◽

Fabiana Geraci

Keyword(s):

Nervous System ◽

Parkinson Disease ◽

Protective Role ◽

Cellular Stress Response ◽

Protective Effects ◽

Older Individuals ◽

Underlying Mechanisms ◽

Cerebral Ischemic

Heat shock proteins (HSPs) are induced in response to many injuries including stroke, neurodegenerative disease, epilepsy, and trauma. The overexpression of one HSP in particular, Hsp70, serves a protective role in several different models of nervous system injury, but has also been linked to a deleterious role in some diseases. Hsp70 functions as a chaperone and protects neurons from protein aggregation and toxicity (Parkinson disease, Alzheimer disease, polyglutamine diseases, and amyotrophic lateral sclerosis), protects cells from apoptosis (Parkinson disease), is a stress marker (temporal lobe epilepsy), protects cells from inflammation (cerebral ischemic injury), has an adjuvant role in antigen presentation and is involved in the immune response in autoimmune disease (multiple sclerosis). The worldwide incidence of neurodegenerative diseases is high. As neurodegenerative diseases disproportionately affect older individuals, disease-related morbidity has increased along with the general increase in longevity. An understanding of the underlying mechanisms that lead to neurodegeneration is key to identifying methods of prevention and treatment. Investigators have observed protective effects of HSPs induced by preconditioning, overexpression, or drugs in a variety of models of brain disease. Experimental data suggest that manipulation of the cellular stress response may offer strategies to protect the brain during progression of neurodegenerative disease.

Peripheral and central glutamate dyshomeostasis in neurodegenerative disorders

Current Neuropharmacology ◽

10.2174/1570159x18666201015161919 ◽

2020 ◽

Vol 18 ◽

Author(s):

Adejoke Y. Onaolapo ◽

Olakunle J. Onaolapo

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Hepatic Encephalopathy ◽

Liver Dysfunction ◽

Liver Enzymes ◽

Excitatory Neurotransmitter ◽

Glutamate Homeostasis

: Glutamate’s role as the major excitatory neurotransmitter of the mammalian central nervous system requires that its brain concentrations be kept tightly-controlled. However, in hepatic encephalopathy resulting from liver dysfunction; disruption of central neurotransmission and elevation of brain glutamate levels have been observed. These had been associated with certain neurological changes. While neurological changes resulting from hepatic encephalopathy are believed to be transient, the discovery of alterations in liver enzymes in Alzheimer’s disease and the role of glutamate and glutamate homeostasis in hepatic encephalopathy have piqued interests on the possible role of glutamate, and glutamate homeostasis in neurodegenerative diseases. Here, we discuss the evidence in support of the involvement of peripheral/central glutamate homeostasis in the development of neurodegenerative disorders as well as the implications of such interactions in the development of new therapies for neurodegenerative disorders.

Genetics of Neurodegenerative Diseases

10.1093/med/9780190233563.003.0010 ◽

2016 ◽

Author(s):

Lynn M. Bekris ◽

James B. Leverenz

Keyword(s):

Genetic Variants ◽

Dementia With Lewy Bodies ◽

Autosomal Dominant ◽

Lewy Bodies ◽

Genetic Knowledge ◽

Dominant Mutation ◽

Time Line

A great deal has been discovered about Neurodegenerative disorders (NDDs) including Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, dementia with Lewy bodies . This includes genetic variants associated with both sporadic and autosomal dominant NDDs. These findings have been crucial in our understanding the underlying factors that drive neuropathological changes and in clarifying the time line of biomarker changes in presymptomatic autosomal dominant mutation carriers. While much is still to be learned, these findings will play an important role in the future of neurodegenerative prediction, diagnosis, and treatment. This chapter summarizes the current genetic knowledge related to both the sporadic and autosomal dominant forms of neurodegenerative disease.

Faculty Opinions recommendation of Molecular pathology of paediatric central nervous system tumours.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726820734.793530284 ◽

2017 ◽

Author(s):

Scott Pomeroy ◽

Soma Sengupta

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Molecular Pathology ◽

Central Nervous System Tumours

Natural Products for the Treatment of Neurodegenerative Diseases

Current Medicinal Chemistry ◽

10.2174/0929867326666190527120614 ◽

2020 ◽

Vol 27 (34) ◽

pp. 5790-5828 ◽

Cited By ~ 1

Author(s):

Ze Wang ◽

Chunyang He ◽

Jing-Shan Shi

Keyword(s):

Nervous System ◽

Natural Products ◽

Neuroprotective Effect ◽

Rapid Development ◽

New Drugs ◽

Progressive Degeneration ◽

Cord Injury ◽

The Central Nervous System ◽

And Function

Neurodegenerative diseases are a heterogeneous group of disorders characterized by the progressive degeneration of the structure and function of the central nervous system or peripheral nervous system. Alzheimer's Disease (AD), Parkinson's Disease (PD) and Spinal Cord Injury (SCI) are the common neurodegenerative diseases, which typically occur in people over the age of 60. With the rapid development of an aged society, over 60 million people worldwide are suffering from these uncurable diseases. Therefore, the search for new drugs and therapeutic methods has become an increasingly important research topic. Natural products especially those from the Traditional Chinese Medicines (TCMs), are the most important sources of drugs, and have received extensive interest among pharmacist. In this review, in order to facilitate further chemical modification of those useful natural products by pharmacists, we will bring together recent studies in single natural compound from TCMs with neuroprotective effect.