Neurodegeneration in the age of molecular biology

Clinicians still think of neurodegenerative disorders in terms of nonspecific, 19th century style palliation. For a few disorders, we can temporarily relieve symptoms by pharmacological or surgical manipulation of the neurotransmitters emitted by the degenerating neurones. In the past decade, thinking about these disorders has been reordered by the discovery that most of them feature excessive protein misfolding and intracellular protein aggregation. This insight could permit us to interrupt the process of neuronal loss itself.

Tau, an important component of cytoskeletal physiology, is the protein that aggregates most commonly in neurodegenerative diseases, both in terms of number of disorders and numbers of patients affected. It forms the neurofibrillary tangles of Alzheimer's disease, Pick's disease, progressive supranuclear palsy, frontotemporal dementia, corticobasal degeneration, postencephalitic parkinsonism, and a handful of others.

Next most common, at least in terms of population prevalence, is β-amyloid, principal component of the amyloid plaques of Alzheimer's disease. Another protein with epidemiological importance is α-synuclein, which forms the aggregates of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and others. Tau and α-synuclein may even interact to increase the risk of Parkinson's disease.¹

The mechanisms by which protein aggregates impair cell function and survival are slowly becoming known. One advanced example is α-synuclein. The normal function of this small protein, still unclear, includes protecting neurotransmitter-laden vesicles and helping to transport them from cell body to synapse. The classic pathogenetic hallmark of Parkinson's disease is the Lewy body, a layered, radially arranged fibrillary aggregate of some two dozen chemical components, chief among which, found in 1997, is α-synuclein.² It seems, however, that Lewy bodies themselves do not damage neurones. Rather, an early stage of aggregate consisting of fewer than 30 α-synuclein molecules, a “protoaggregate” or “oligomer,” is probably the offending species. It may exert its toxic action by creating pores in lipid membranes.³ One result is leakage of dopamine from vesicles into the cytoplasm. Free dopamine, aside from its direct oxidative toxicity, exacerbates the pathogenetic process by inhibiting the further aggregation of the protoaggregates into Lewy bodies.⁴ By sequestering the protoaggregates, the Lewy bodies may provide a protective function. The story for the other neurodegenerative disorders may be variations on the theme of protoaggregates producing toxicity and mature aggregates providing a means of sequestering them.

Underlying this story for most neurodegenerative disorders is abnormal protein folding.⁵ This exposes hydrophobic regions, permitting aggregation. The cell's principal means of disposing of abnormally folded proteins is the ubiquitin-proteasome system. Protein aggregates themselves can impair the function of that system, probably by a simple clogging mechanism.⁶ At least one neurodegenerative disorder, autosomal recessive juvenile parkinsonism, is caused by a genetic defect in a component of that system, parkin.⁷

The causes of the abnormal folding are various and still poorly understood. Obvious causes are genetic defects producing a single amino acid substitution or expansion of a repeating amino acid tract, as occurs in the strongly familial forms of many neurodegenerative diseases.⁸,⁹ However, for most neurodegenerative disorders that occur sporadically or in non-Mendelian familial fashion, other causes of abnormal folding lie at the source of the pathogenetic cascade.

For example, again in the case of non-familial Parkinson's disease, exposure to pesticides,¹⁰ certain metals,¹¹ or oxidative stress (probably via mitochondrial defects)¹² can cause abnormal α-synuclein folding and subsequent aggregation. Genetically determined variation in the ability to degrade exogenous toxins enzymatically or compensate for oxidative stress may be central to susceptibility to disease and to determination of the age of onset.

Introducing the concept of protein aggregation into our thinking will also allow us to transcend the classic rubric of clinical and anatomical pathology. An excellent example is the obsolescence of the term olivopontocerebellar atrophy. The sporadic form of olivopontocerebellar atrophy has been found to harbour cytoplasmic inclusions in oligodendrocytes consisting chiefly of α-synuclein. The same is true for Shy-Drager syndrome and striatonigral degeneration.¹³ These three entities have now been combined into a pathogenetically based rubric called multiple system atrophy. The familial form of olivopontocerebellar atrophy has been subsumed into the various forms of spinocerebellar ataxia, which are differentiated by their genetic defects and by the nature of their protein aggregates. The term olivopontocerebellar atrophy has therefore proved useless and has virtually disappeared from the literature.

As we consider the pathogenesis and classification of neurodegenerative disease, we must consider the identity of the abnormally aggregating protein, the cause of its misfolding, causes of protein aggregation other than misfolding, the causes of failure of the ubiquitin-proteasome system to dispose of the abnormally folded or aggregated protein, and the mechanism by which abnormally aggregated protein causes cellular damage. This framework will bring a more rational classification of disease and a very high probability of specific treatments or prevention.