Chapter 9

DEGENERATIVE DISEASES

The degenerative diseases are characterized clinically by loss of neurological function (dementia, loss of movement control, paralysis), and pathologically by loss of neurons. In some of them, loss of neurons is accompanied by specific histopathological findings such as Alzheimer's plaques and Lewy bodies. Others show gradual neuronal atrophy and loss, without specific pathology. Some degenerative diseases involve specific anatomical systems or interconnected sets of neurons. The pathology is either diffuse or, when it is focal, is bilateral and symmetric. Degenerative diseases are inexorably progressive. Most of them are diseases of old age, but some involve young people, including children. The term "degenerative" or "neurodegenerative," is vague. It is now becoming clear that degenerative diseases have a biochemical basis. Many degenerative diseases are inherited. Their genes are known and DNA-based diagnosis (including prenatal diagnosis) is available in many of them. More information about the gene products and understanding of pathophysiological mechanisms will open the way to specific treatments. The most common degenerative disease is Alzheimer's disease and the second most frequent is Parkinson's disease.

DEMENTIA

Dementia (loss of mental power) is a generic term, not a disease entity. Any pathology that causes significant brain damage, at any age, can cause dementia. The causes of dementia include:

Stroke and ischemic encephalopathy (multi-infarct or vascular dementia)
Hippocampal sclerosis
Head trauma (subdural hematomas, diffuse axonal injury, chronic traumatic encephalopathy)
Hydrocephalus
CNS infections (HIV encephalitis, Creutzfeldt-Jakob disease)
Metabolic CNS disorders
(lysosomal storage and peroxisomal diseases) Demyelinative diseases (multiple sclerosis)
Neurodegenerative diseases
(Alzheimer's disease, Parkinson's disease, diffuse Lewy body dementia, Huntington's disease, and other)
Neuropsychiatric disorders
Severe medical illness or organ failure
The effects of medications

DEGENERATIVE DISEASES AS PROTEINOPATHIES

Central to the pathology and pathogenesis of degenerative diseases is the deposition of abnormal proteins in the brain. In some diseases, normally soluble proteins misfold into a beta-pleated pattern and change into insoluble fibrillary amyloid. These deposits can be identified in tissue sections, frequently bound to ubiquitin, and are specific for certain groups of disorders. The table below lists the major proteinopathies.

PROTEIN DISEASE LOCATION AND FORM OF DEPOSITS
Beta amyloid AD Extracellular-amyloid (SPs)
Tau AD, FTLD NFTs and other neuronal and glial inclusions
TDP-43 FTLD, ALS Neuronal and glial inclusions
alpha-synuclein PD, DLBD Neuronal inclusions-Lewy bodies
Polyglutamine-expanded
(polyQ) proteins
HD,
spinocerebellar ataxias
Intranuclear and cytoplasmic
Prion protein CJD, other prion diseases Extracellular-amyloid

AD: Alzheimer's disease; ALS: Amyotrophic lateral sclerosis; DLBD: Diffuse Lewy body disease; CJD: Creutzfeldt-Jacob disease; FTLD: Frontotemporal lobar degeneration; HD: Huntington's disease; NFT: Neurofibrillary tangle; PD: Parkinson's disease; SP: Senile plaque

THE UBIQITIN-PROTEASOME  AND LYSOSOMAL SYSTEM IN NEURODEGENERATIVE DISEASES

Protein recycling in cells is done by 2 systems, the ubiquitin-proteasome system (UPS) and the lysosomal system. The UPS consists of the proteasome, a barrel-shaped multi-enzyme complex, and  ubiquitin, a small protein that tags proteins targeted for proteasomal degradation. The UPS degrades abnormal and damaged proteins and regulates also the turnover of normal short-lived proteins that are important for regulation of cell function. Abnormal forms of proteins, including tau, huntingtin, and mutant synuclein, form aggregates that cannot be digested in proteasomes and accumulate in the cytoplasm or nucleus in the form of inclusions. Such aggregates damage the UPS. Proteolysis in the UPS plays an important physiological role in growth and remodeling of axons, dendrites, and synapses. Impairment of the UPS is seen in several neurodegenerative diseases, including AD, Parkinson's disease, Huntington's disease, other CAG trinucleotide repeat disorders, and ALS.
Lysosomes degrade long-lived proteins, chunks of cytoplasm, and entire organelles. These functions protect cells from accumulation of damaged organelles that could induce apoptosis, remove metabolic waste, and help cells survive and adapt to changes in their environment. Abnormally folded proteins that occur in neurodegenerative diseases are processed through lysosomes. Accumulation of such products and of lipofuscin, impairs lysosomal function.
Proteolytic activity (and the ability for cell renewal) decline with advancing age. This is probably responsible for the clinical onset of neurodegenerative diseases in old people.

A history of dementia and its possible genetic implications is one of the most frequent reasons why an autopsy is done today. Dementia is easy to diagnose clinically but there are no reliable clinical or laboratory tests for determining if its is caused by Alzheimer's disease (AD) or another entity. In most cases, examination of brain tissue is the only way to answer this question. The autopsy is the foundation of our knowledge of Alzheimer's disease and other degenerative diseases. As we learn more about the various degenerative dementias, the role of the autopsy has become even more important. The vast majority of patients who come to autopsy with the primary diagnosis of dementia turn out to have a neurodegenerative disease, usually AD. A small proportion have multi-infarct dementia. Some patients have more than one disease contributing to the dementia, e.g. AD, MS, and multiple strokes.


Updated: May, 2012

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