The clinical features of Parkinson’s disease are most commonly due to Lewy body pathology, but can also be caused by multiple system atrophy or by several disorders characterized by neurofibrillary tangle formation.

 The syndrome of progressive supranuclear palsy can be associated with neurofibrillary tangles in neurons, Lewy body pathology, or cerebrovascular disease.

 The syndrome of frontotemporal dementia can be associated with several distinct neuropathologic patterns of neurodegenerative disease.

 The entity of multiple system atrophy as defined by the presence of large numbers of glial cytoplasmic inclusions can present with parkinsonism, laryngeal palsy, autonomic failure, cerebellar ataxia, or a combination of features.

 Lewy body pathology can cause Parkinson’s disease, dementia, autonomic failure, focal dystonia, or isolated dysphagia.

PROTEIN ACCUMULATION AND DEGRADATION

These are key features of several neurodegenerative diseases. The accumulations of abnormal proteins occur either intracellularly as inclusion bodies or extracellularly, usually as amyloid. Cellular inclusion bodies have long been recognized as characteristic of certain degenerative processes, and in many cases are required features for the histologic diagnosis of specific diseases. Important examples of such inclusions are:

Most inclusions were originally defined by special tinctorial staining techniques. Cellular and molecular biologic studies have characterized the constituent proteins of many inclusions and defined some of the steps involved in their biogenesis. Some of the intracellular inclusions of degenerative diseases are derived from cytoskeletal or cytoskeleton-related proteins, in many instances modified by abnormal patterns of phosphorylation and other post-translational processes. It is now becoming common for neurodegenerative diseases to be named according to the protein involved, for example synucleinopathy, tauopathy.

In certain diseases, mutations in the genes coding for specific proteins leads directly to their accumulation in inclusion bodies. Tau protein accumulates in neuronal and glial cells in a variety of neurodegenerative diseases, some of which are now recognized to be associated with mutations in the tau gene (MAPT), on chromosome 17. These insights have led to the collective designation of these conditions as tauopathies, some of which are familial and some sporadic. There are several isoforms of tau, formed by differential splicing. Of particular relevance in neurodegenerative disease is the difference between the forms of tau with three and those with four microtubule-binding domains. Alzheimer’s disease is the commonest condition characterized by tau protein accumulation but is not linked to MAPT mutations, and is hence an example of a sporadic tauopathy. Other sporadic conditions characterized by tau protein accumulation in neurons or glia include progressive supranuclear palsy, corticobasal degeneration, and grain dementia. A subgroup of the frontotemporal lobar degenerations is linked to mutations in the tau gene, and certain haplotypes of the tau gene are associated with progressive supranuclear palsy.

Transactivation response DNA binding protein 43 (TDP43) is normally located in the nucleus of cells and acts as a transcriptional regulator. This protein has been found to be the main constituent of inclusion bodies in amyotrophic lateral sclerosis/motor neuron disease, and in some of the cases of frontotemporal lobar degeneration.

α-synuclein is a normal synaptic protein which has been recognized to be a major constituent of Lewy bodies in Parkinson’s disease and glial cytoplasmic inclusions in multiple system atrophy. In most cases, there is no mutation in the α-synuclein gene but this gene is mutated in rare familial forms of Parkinson’s disease. These conditions have been collectively termed synucleinopathies. There are also other, much rarer diseases associated with α-synuclein inclusion bodies (such as some forms of neuroaxonal dystrophy, and diffuse neurofibrillary tangles with calcification – a disease in which both tau and α-synuclein inclusions are present).

In diseases which are caused by triplet repeat expansions of CAG repeats, such as Huntington disease and some spinocerebellar degenerations, inclusions composed of polyglutamine, coded by a CAG repeat, develop within neuronal nuclei. These disorders have been referred to as the polyglutamine disorders.

The prion diseases (see Chapter 32) represent a biological phenomenon that is probably unique in which a protein-only transmissible agent is responsible for disease.

In many inclusion bodies, a common factor is accumulation of the protein ubiquitin, together with other proteins that are part of the ubiquitin-proteasome system (UPS), for example P62 (sequestosome 1). This system normally functions to eliminate short-lived or misfolded proteins. The present of UPS proteins in many different types of inclusion probably represents a cellular response aimed at the elimination of abnormal proteins. In some familial neurodegenerative diseases, mutations in genes coding for proteins involved in the UPS have been found, suggesting that inefficiencies in protein degradation can lead to neurodegeneration. Abnormalities in autophagic pathways and endosomal recycling may also contribute to the pathogenesis of this group of diseases.

A practical consequence of these insights is the increasing use of specific immunohistochemical techniques rather than empirical stains such as various types of silver impregnation to detect inclusions. Immunohistochemical detection of phosphorylated tau protein, α-synuclein, TDP43, P62 and ubiquitin are now routinely used to establish a histological diagnosis in many neurodegenerative diseases.

The accumulation of abnormal extracellular proteins in the form of amyloid is a characteristic feature of Alzheimer’s disease as well as prion diseases. The pathogenesis of the accumulation of amyloid is beginning to be uncovered. Amyloids are extracellular fibrillar proteins defined by their physicochemical characteristics, including: