An Historical Overview of the Amyloidoses

The amyloidoses are a heterogenous group of clinical disorders that share the common finding of the abnormal deposition of insoluble proteins into various organs, with the result that these proteinaceous deposits disrupt cellular function and impair the integrity of the organs involved. Most typically, the abnormal protein deposition is the consequence of abnormal three dimensional folding of the culprit protein. The abnormal folding of the protein, in turn, may be due to a germ line mutation, may be due to an acquired mutation, or may be due to a polymorphism or characteristic of a normal protein that leads to abnormal folding, precipitation, and deposition of the protein, particularly when that protein is expressed at unusually high levels for a prolonged period of time. The clinical manifestations of an amyloid disorder are the consequences of the array of organs involved, the extent of amyloid deposition, and co-morbid conditions present in the individual patient. The array of organs involved, and the extent of organ involvement, in turn, depend in large part on the specific protein that is responsible for the amyloid deposition, and the process driving that protein’s production. In this chapter, a chronological overview is intended to summarize the critical insights into the patho-biology of amyloid accumulation of various types. These insights have allowed an improved understanding over time of the of the major subgroups and disease entities of the amyloidoses, leading to some degree of improvement in diagnosis and treatment outcomes. Unfortunately, as of this writing, treatment outcomes still remain poor for a large fraction of patients, and there is need for improvement in all aspects of the evaluation and management of these diseases

Transcription Factors Analysis in Neuronal-Like Cells Derived from Adult Human Bone Marrow.

Abstract Stem cells are immature cells with self-renewal capacity and ability to differentiate into multiple cell types including bone, cartilage, fat, tendon and muscle. Transplantation of stem cells or their derivatives to the adult brain have been proposed as future therapy for neurodegenerative diseases. Parkinson’s disease (PD) is a progressive neurodegenerative disease involving the deterioration of dopaminergic neurons of the substantia nigra, a part of the midbrain. Most of the currently used drugs are based on dopamine replacement which, although it reduces symptoms is limited owing to severe side effects. Alternatively, strategies of cell therapy for the treatment of PD focused on replacing damaged neurons with cells that may improve the functioning of the damaged cell population. In this study, we demonstrate that bone marrow stromal cells isolated from human iliac crest can be induced to differentiate into neural-like cells. Human bone marrow stromal cells differentiation was induced with N2 supplements, retinoic acid, butylated hydroxyanisole, isobutylmethylxanthine and dibutyryl-cyclic-AMP. A few hours after differentiation the cells changed their phenotype to neural-like cells, spindle shaped, with cell bodies and long branches. Moreover, immunostaining demonstrated the expression of specific neuronal markers such as nestin, neurofilaments and neuron specific enolase. To define the transcription factors associated with the differentiation, we used the TranSignal Protein/DNA kit (Panomics Inc). This new array-based technology allows functional analysis of dozens of eukaryotic transcription factors. Nuclear proteins were purified and incubated with mix labeled DNA binding oligonucleotides corresponding to the consensus sequences of 96 transcription factors. The DNA probes were then dissociated from the complexes and used to hybridize the TranSignal Array. We found that the differentiated human bone marrow stromal cells induced the expression of several neuron-specific transcription factors such as GAG (glycosaminoglycan), FKHR (human forkhead in rhabdomyosarcoma) and DR-2. The activation of these transcription factors in a time course manner was evident also by electrophoretic mobility shift assay. In conclusion, we show that the induced differentiation of neuronal like cells from bone marrow is associated with activation of specific neuronal transcription factors. Our study advances the possible use of autologous transplantation as a new strategy for cell therapy in neurodegenerative diseases.</jats:p