Protein toxicity: protein aggregation and prion domains

1 7 6 7 jci.org Volume 125 Number 5 May 2015 Introduction Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disorder of motor neurons that begins focally and spreads, leading to weakness of limb, respiratory, and bulbar muscles. Immediately preceding death, there is a near total loss of limb and respiratory function, as well as a loss of the ability to chew, swallow, and speak. ALS is defined as an “orphan disease,” with approximately 2 per 100,000 new cases per year and a prevalence of about 5 per 100,000 total cases each year (1). In the United States (2) and Europe (3, 4), ALS is diagnosed in about 1 in 500 to 1 in 1,000 adult deaths, implying that 500,000 people in the United States will develop this disease in their lifetimes. About 10% of ALS cases are inherited, usually as dominant traits (5, 6). Both familial ALS (fALS) and sporadic ALS (sALS) can develop concurrently with frontotemporal lobar dementia (FTLD). By contrast with the dementia of Alzheimer disease (AD), in which the cardinal finding is memory loss, FTLD is characterized by behavioral changes and progressive aphasia, sometimes accompanied by movement disorders (7, 8). While AD involves prominent pathology in the hippocampus, the essential finding in FTLD is, as the name suggests, early atrophy of the frontal and temporal lobes. Four recurring themes have emerged from the pathological analysis of autopsied cases with sALS, fALS, or ALS-FTLD with diverse genetic causes. First, the motor neuron death usually entails deposition of aggregated proteins, often ubiquitinated and predominantly cytoplasmic. Second, in ALS, the levels and functions of RNA and RNA-binding proteins are abnormal. Aggregates of protein and RNA are detected both in motor neurons and nonneuronal cells, such as astrocytes and microglia. Third, most cases entail some disturbance of neuronal cytoskeletal architecture and function. Additionally, in almost all cases, motor neuron death is influenced by non-neuronal cells, including oligodendroglia and cells involved in neuroinflamation (e.g., astroglia and microglia). Protein toxicity: protein aggregation and prion domains An important theme in ALS pathogenesis is that several species of protein (both WT and mutant) are dysfunctional in both fALS and sALS, as evidenced by the formation of aggregates, abnormal cleavage events, or distinctive posttranslational modifications (e.g., ubiquitination or hyperphosphorylation). These changes occur both as primary consequences of mutations in the affected proteins and as secondary phenomena induced by the underlying disease process. Protein aggregation and inclusion bodies. It has been apparent for decades that protein pathology is important in ALS, as suggested by an early pathological finding of deposition of threads of ubiquitinated material in motor neurons (9). This has been interpreted as denoting the presence of proteins that are conformationally unstable or modified, and so are destined for degradation. In later stages of motor neuron disease, dense aggregates of ubiquitinated protein are seen, sometimes in association with eosinophilic aggregates described as “Bunina bodies” (10). Whether these deposits are toxic or reflect a cellular response to a more primary pathology remains unclear. Indeed, the possibility that some aggregates may reflect beneficial, compensatory events has also been considered. Cytosolic superoxide dismutase [Cu/Zn] (SOD1) was the first gene and protein whose mutations were demonstrated to cause ALS (Table 1; ref. 11). Of the more than 160 different missense and 12 truncation mutations detected in SOD1 (12), most impair conformational stability of this abundant protein, triggering its deposition in inclusion bodies within spinal motor neurons (13) both in vitro and in vivo (14, 15). There is a general correlation between the degree of mutation-induced conformational instability and the rate of clinical progression (15). Mutant SOD1 also spontaneously forms oligomers in vivo and in vitro (16, 17) that are submicroscopic and often soluble (18) and may be more toxic than larger, visible aggregates (19, 20). Aggregates of posttranslationally modified WT SOD1 can also be detected in the spinal cords of many sALS patients (21–23). This Amyotrophic lateral sclerosis (ALS) is a devastating degenerative disease characterized by progressive loss of motor neurons in the motor cortex, brainstem, and spinal cord. Although defined as a motor disorder, ALS can arise concurrently with frontotemporal lobal dementia (FTLD). ALS begins focally but disseminates to cause paralysis and death. About 10% of ALS cases are caused by gene mutations, and more than 40 ALS-associated genes have been identified. While important questions about the biology of this disease remain unanswered, investigations of ALS genes have delineated pathogenic roles for (a) perturbations in protein stability and degradation, (b) altered homeostasis of critical RNAand DNA-binding proteins, (c) impaired cytoskeleton function, and (d) non-neuronal cells as modifiers of the ALS phenotype. The rapidity of progress in ALS genetics and the subsequent acquisition of insights into the molecular biology of these genes provide grounds for optimism that meaningful therapies for ALS are attainable. Emerging mechanisms of molecular pathology in ALS