Amyotrophic Lateral Sclerosis Associated with Genetic Abnormalities in the Gene Encoding Cu/Zn Superoxide Dismutase: Molecular Pathology of Five New Cases, and Comparison with Previous Reports and 73 Sporadic Cases of ALS

Abstract

Molecular pathology has identified 2 distinct forms of neuronal inclusion body in Amyotrophic Lateral Sclerosis (ALS). ALS-type inclusions are skeins or small dense filamentous aggregates which can only be demonstrated by ubiquitin immunocytochemistry (ICC). In contrast hyaline conglomerates (HC) are large multifocal accumulations of neurofilaments. Previous reports have failed to clarify the distinction and relationship between these inclusions. Correlation of molecular pathology with sporadic and familial cases of ALS will detect specific associations between molecular lesions and defined genetic abnormalities; and determine the relevance of molecular events in familial cases to the pathogenesis of sporadic disease. We describe the molecular pathology of 5 ALS cases linked to abnormalities of the SOD1 gene, in comparison with a series of 73 sporadic cases in which SOD1-gene abnormalities were excluded. Hyaline conglomerate inclusions were detected only in the 2 cases with the SOD1 I113T mutation and showed a widespread multisystem distribution. In contrast ALS-type inclusions characterized sporadic cases (70/73) and were restricted to lower motor neurons. Hyaline conglomerates were not seen in sproadic cases. Confocal microscopic analysis and ICC shows that HC contain equally abundant phosphorylated and nonphosphorylated neurofilament epitopes, indicating that phosphorylation is not essential for their formation. In contrast neurofilament immunoreactivity is virtually absent from typical ALS-type inclusions. The SOD1-related cases all had marked corticospinal tract and dorsal column myelin loss. In 4 cases the motor cortex was normal or only minimally affected. This further illustrates the extent to which upper motor neuron damage in ALS is usually a distal axonopathy. Previously reported pathological accounts of SOD1-related familial ALS (FALS) are reviewed. Hyaline conglomerates are so far described in cases with mutations A4V, I113T and H48Q. In only 1 of 12 cases (H48Q) reported were both HC and ALS-type inclusions present in the same case. These findings suggest the possibility that the molecular pathology of neuronal inclusions in ALS indicates 2 distinct pathogenetic cascades.

A4T Mutation in the <i>SOD1</i> Gene Causing Familial Amyotrophic Lateral Sclerosis

“…Lower motor neuron signs have been predominant. This confirms the observation that 'codon 4 FALS' is characterised by the progressive muscular atrophy (PMA) form of ALS [11,12]. The mean survival in the PMA form of ALS is 159 months [13], which is in striking contrast to the patients in this study.…”

Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis

“…Postmortem examination of ALS patient tissues reveals an obvious loss of motor neurons in the central nervous system (CNS), while many remaining neurons demonstrate central chromatolysis, numerous inclusions, swelling of the perikaryon and proximal axon, mitochondria swellings, vacuoles, and neurofilament accumulations [26]. Intracellular inclusions of ubiquitinated misfolded proteins, including transactive response DNA binding protein 43 kDa, SOD1, phosphorylated neurofiliaments, fused in sarcoma, and/or cystatin C occur in both hereditary and nonhereditary cases, and are a pathologic hallmark of disease [27][28][29][30][31][32]. The processes involved in motor neuron injury can be further categorized into mechanisms that are "cell autonomous" occurring within the motor neuron, and "noncell autonomous" involving multiple non-neuronal cells contributing to the disease process [33].…”

Developmental and Functional Nature of Human iPSC Derived Motoneurons

“…ALS is the most common adult onset disorder of motoneurons with an incidence of 1-3 per 100.000 year [172] and has been described as early as 1869 by JeanMarie Charcot depicting the clinical phenotype of ALS-patients for the first time [84]. ALS is characterized by degeneration of both the lower motoneurons in the spinal cord and brain stem as well as of the upper motoneurons in the motor cortex [21,172].…”