The cause of neurodegeneration in Huntington's disease (HD) is unknown. Patients with HD have an expanded NH2-terminal polyglutamine region in huntingtin. An NH2-terminal fragment of mutant huntingtin was localized to neuronal intranuclear inclusions (NIIs) and dystrophic neurites (DNs) in the HD cortex and striatum, which are affected in HD, and polyglutamine length influenced the extent of huntingtin accumulation in these structures. Ubiquitin was also found in NIIs and DNs, which suggests that abnormal huntingtin is targeted for proteolysis but is resistant to removal. The aggregation of mutant huntingtin may be part of the pathogenic mechanism in HD.

https://science.sciencemag.org/content/sci/277/5334/1990.full.pdf

Aggregation of Huntingtin in Neuronal Intranuclear Inclusions and Dystrophic Neurites in Brain

TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the hd mutation

▪ Abstract Prion diseases are transmissible neurodegenerative conditions that include Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE) and scrapie in animals. Prions appear to be composed principally or entirely of abnormal isoforms of a host-encoded glycoprotein, prion protein. Prion propagation involves recruitment of host cellular prion protein, composed primarily of α-helical structure, into a disease specific isoform rich in β-sheet structure. The existence of multiple prion strains has been difficult to explain in terms of a protein-only infections agent, but recent studies suggest that strain specific phenotypes can be encoded by different prion protein conformations and glycosylation patterns. The ability of a protein to encode phenotypic information has important biological implications. The appearance of a novel human prion disease, variant CJD, and the clear experimental evidence that it is caused by exposure to BSE has highlighted the need to understand the ...

Prion Diseases of Humans and Animals: Their Causes and Molecular Basis

As there are no biological markers for the antemortem diagnosis of degenerative parkinsonian disorders, diagnosis currently relies upon the presence and progression of clinical features and confirmation depends on neuropathology. Clinicopathologic studies have shown significant false-positive and false-negative rates for diagnosing these disorders, and misdiagnosis is especially common during the early stages of these diseases. It is important to establish a set of widely accepted diagnostic criteria for these disorders that may be applied and reproduced in a blinded fashion. This review summarizes the findings of the SIC Task Force for the study of diagnostic criteria for parkinsonian disorders in the areas of Parkinson's disease, dementia with Lewy bodies, progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration. In each of these areas, diagnosis continues to rest on clinical findings and the judicious use of ancillary studies.

/pdf/sic-task-force-appraisal-of-clinical-diagnostic-criteria-for-2mntcoyjd5.pdf

SIC Task Force appraisal of clinical diagnostic criteria for parkinsonian disorders

A filamentous inclusion body within anterior horn neurones in motor neurone disease defined by immunocytochemical localisation of ubiquitin.

Motor neurone disease-inclusion dementia.

alpha B crystallin is a protein which has homology with the small cell stress proteins. A characterized antibody to residues 1-10 of alpha B crystallin was used to immunostain tissues containing ballooned (chromatolytic, achromasic) neurons. The tissues included two cases of classical Pick's disease, one case of dementia with swollen achromasic neurons in the cortex, two cases of Alzheimer's disease with large numbers of ballooned neurons, two cases of motor neuron disease, four cases of cortico-basal degeneration, and four cases with areas of brain showing swollen neurons adjacent to recent cerebral infarcts. The anti-alpha B crystallin showed strong diffuse cytoplasmic immunoreactivity of swollen cortical neurons in all the diseases. Astrocytes and oligodendroglial cells were also stained in normal tissues as previously described. Weak diffuse immunoreactivity with an antibody to ubiquitin-conjugates was also seen in the swollen neurons from cases of neurodegenerative disease but not following infarction. Ballooned neurons have been shown to contain phosphorylated neurofilament epitopes not normally present in the perikaryonal region. The presence of alpha B crystallin in ballooned neurons, together with previous data which also indicate its close association with intermediate filaments, suggest that alpha B crystallin may be involved in aggregation and remodelling of neurofilaments in disease. The presence of alpha B crystallin in neurons at the edge of areas of cerebral infarction is likely to reflect cells which are regenerating following damage; its detection may therefore be a marker for such cells. On a practical level, the antibody greatly facilitates the localization of such abnormal neurons in diagnostic histology.

Ballooned neurons in several neurodegenerative diseases and stroke contain αB crystallin

We have studied the brains of 10 patients with clinically and pathologically defined Huntington's disease and graded the degree of striatal pathology according to the Vonsattel grading system. Sections from nine cerebral cortical areas (Brodmann areas 8. 10, 24, 33, 28, 38, 7, 39, 18), the cerebellum, hypothalamus, medulla and caudate nucleus were stained with antibodies to ubiquitin and ubiquitin C-terminal hydrolase (PGP 9.5). Dystrophic neurites. immunoreactive with ubiquitin and PGP 9.5 were detected in all cortical areas. in layers 3, 5 and 6, of all brains studied. No dystrophic neurites were found in subcortical areas or cerebellum. Sections from cortical areas 8 and 24 from the two brains with the most and least ubiquitin-immunoreactive neurites were stained with antibodies to β-amyloid precursor protein, tau, glial fibrillary acidic protein, neurofilament protein, αB crystallin, GABA, cholecystokinin and somatostatin. The dystrophic neurites were found to also react with β-amyloid precursor protein. Electron microscopy showed the abnormal neurites to contain granulo-filamentous material. Granular deposits with a diameter of 40–100 nm were interspersed between randomly orientated ‘fuzzy’ or coated, straight or slightlv curved filaments measuring 10–15 nm in diameter. These structures have not been seen in control brain and differ from age-related neuritic degeneration and neurites associated with amyloid. Immunohistochemically these structures most resemble CA 2/3 neurites seen in Lewy body disease, and, ultrastructurally, the intraneuronal filamentous inclusions in motor neuron disease. The areal density of these neurites was quantified in 20 microscopic fields in the superior frontal and anterior cingulate sections (Brodmann areas 8 and 24) and did not correlate with the Vonsattel grade, suggesting that they are an independent and possibly primary cortical pathology in Huntington's disease.

/pdf/the-cortical-neuritic-pathology-of-huntington-s-disease-3jhbmeh15g.pdf

G. Lennox

Papers

A filamentous inclusion body within anterior horn neurones in motor neurone disease defined by immunocytochemical localisation of ubiquitin.

Motor neurone disease-inclusion dementia.

Ballooned neurons in several neurodegenerative diseases and stroke contain αB crystallin

The cortical neuritic pathology of Huntington's disease

Dementia Associated with Cortical Lewy Bodies: Proposed Clinical Diagnostic Criteria